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"Caffeine Salicylate" - A Novel Compound?

Discussion in 'Supplements' started by Sativa, Aug 3, 2019.

  1. Sativa

    Sativa Member

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    I have been experimenting with creating Sodium & Magnesium salts of Salicylic acid (see this thread).
    I then had the idea to combine two Peat favourites - Caffeine & Salicylic acid!

    The procedure for making Caffeine Salicylate is quite straight-forward.
    You'll need pure Caffeine powder & Salicylic acid powder - both OTC & easily available.

    upload_2019-8-3_23-46-39.png
    Note: You can adjust the weights to something more practical, just ensure you keep the same ratio.
    (eg; increase above mg weights by factor 100 = 5g Caffeine, 3.7g SA)

    I've attached a PDF detailing a lab method for creating this compound, as another example of the process (CaffeineSalicylateLab.pdf). It uses some non-OTC chemicals for the re-crystallization step; which I intend to bypass, opting for basic evaporation instead. I will probably use IPA/ethanol/water.

    Here is the Pubchem entry for Caffeine Salicylate: Caffeine salicylate

    Here is the abstract of a paper which uses this compound (PDF attached - Theraputic effects of Caffeine Salicylate.pdf).

    Enhancement in Cortical Arousal by Caffeine Salicylate in Experimental Animal Models

    Objective: It is aimed to evaluate contribution of two molecules of Caffeine salicylate, a combinatorial product, in the CNS stimulant, anti-inflammatory and an analgesic property in experimental animal models.
    Material and Methods: Caffeine salicylate is synthesized by one step reaction from caffeine and salicylic acid. Actophotometer and open field test were used for the CNS stimulant activity whereas formalin induced rat paw edema and tail immersion test were used to evaluate anti-inflammatory and analgesic properties in experimental animals.
    Results: The locomotor activity was increased from 37.1% for caffeine to 49.24% for caffeine salicylate. In open field test; number of crossing and rearing were increased from 42.34 % to 54.89% and 17.26% to 27.87% respectively. The % inhibition on rat paw edema 16.40% and 18.75% with caffeine salicylate as against diclofinac 51.0% and 62.5% at 60 and 120 min. respectively. The tail withdrawal time was prolonged by 25% with caffeine salicylate as against 78.88 % with pentazocine in wistar rats. The results of all experimental animal models were statistically significant.
    Conclusion: The enhancement in the cortical arousal by caffeine salicylate over caffeine may be due to contribution of antioxidant property of salicylate besides adenosine antagonism and mobilization of intracellular calcium induced dopamine release by caffeine portion of caffeine salicylate. The mild analgesic and anti-inflammatory activities of caffeine salicylate may be due to inhibition of prostaglandin synthesis and an antioxidant properties of salicylate portion of caffeine salicylate.
    [source]


    Q: What's this acid + base chemical reaction all about then?
    As an example of the acid + base procedure; to make the Sodium salt of Salicylic Acid (aka sodium salicylate):
    I mix SA & Sodium bicarbonate in water, stirred every few hours (whenever I remember) to speed up the reaction.
    After the bubbles disappear & fizzing stops, I pour the solution into a Pyrex dish & evaporate in an oven at medium/low temperature (keeping a close eye on things to ensure no burning etc)
    I then scrape up the dried somewhat fluffy NaSali crystals & store in an airtight jar.
    Mine were 80-90% dry when I stored them. I use them in a simple water tincture + pipette.
    Quite straight-forward!

    ...I used 138 grams of salicylic acid from the drugstore and 84 grams of baking soda.
    This yielded 160 (theoretical) grams of sodium salicylate, 18 grams of CO2, and 48 grams of water.
    ...I dissolved the baking soda in warm water, and added the salicylic acid bit by bit.
    Several additions were made, allowing the production of gas to stop in between to prevent overflowing.
     

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  2. lampofred

    lampofred Member

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    Ha I love these science experiment threads.

    If you can find a specific purpose for this, something it does different/better than just caffeine and aspirin taken separately, you could probably patent it like Peat did with Progest-E and sell it...
     
  3. OP
    Sativa

    Sativa Member

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    Note - Aspirin is acetylsalicylic acid (ASA), I prefer to use salicylic acid (SA) - this avoids having an acetyl- group floating around, as well as speeding up the metabolism of SA since there's no need to remove the acetyl- group from SA.

    I am mainly fueled by experimentation...i'm not really bothered about patenting anything...
    btw, I don't even drink coffee!

    I have been enjoying taking my diy Sodium Salicylate - especially for its anti-cortisol properties. I've also been using pure & natural Vit E oil + Squalene, olive oil derived (its a cool cholesterol precursor)
    I've got 10g pure Methylene Blue arriving soon... i'm contemplating what chemistry I can do with that...
     
  4. lampofred

    lampofred Member

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    Well if you find some unique health promoting use for it, then making it popular and selling it at a reasonable price would be a service to people, not a money grab. Like Haidut's supplements.

    But only if it does something that caffeine and salicylic acid can't do individually.
     
  5. OP
    Sativa

    Sativa Member

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    Sounds good.
    Well, if anyone knows... let me know!
    Aside from some papers, I haven't found any information on the human use of Caffeine salicylate...

    The paper I linked might offer some insight into the therapeutic potential of Caffeine salicylate actually:
    Essentially a combination of the properties of both molecules.
    Perhaps having them in a combined form alters the metabolism of each...

    Perhaps @haidut might have some insight...
     
  6. lampofred

    lampofred Member

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    I love your posts, they remind me of visionofstrength's posts...

    I don't have any pure powders but I'm going to go mix various combos of aspirin, Vitamin D, methylene blue, sodium chlorite, salt, hydrochloric acid, etc. and see if I get any cool bubbles...
     
  7. haidut

    haidut Member

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    I think it is a great experiment, but like any salts, upon ingestion the mixture is likely quickly hydrolyzed back into caffeine and salicylic acid. So, orally it will probably be quite similar to taking caffeine and aspirin together as separate ingredients. Since skin has less of a tendency to metabolize salts, it would be interesting to try it topically.
    As far as the cortisol-blocking effects - any type of salicylic acid derivative that metabolizes back into salicylic acid would have this effect. So, aspirin, pure salicylic acid, magnesium/sodium/potassium salts, etc would all have this effect. Salicylic acid is the molecule that inhibits the synthesis of cortisol.
    Salicylate Downregulates 11β-HSD1 Expression in Adipose Tissue in Obese Mice and in Humans, Mediating Insulin Sensitization
     
  8. OP
    Sativa

    Sativa Member

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    Ah - makes sense.
    Perhaps, upon hydrolyzation, the close proximity of both components might elicit an influence upon their pharmacodynamics etc? just a thought.

    I'm also contemplating other Caffeine salts, eg ascorbate, gluconate, bicarbonate, acetate etc... and also other amines!

    eg, Agmatine. It has some extensive pharmacology going on, interacting with multiple areas, including NO, sigma receptors & mitochondria enhancement, if i remember correctly. Available as the sulfate salt; perhaps it has potential.
    So, a potential strategic solution to mitigate polyamine formation from oral agmatine metabolism would be to increase methylglyoxal, either via glyoxylase I inhibitors or:


    And finally, some papers on Agmatine:

    Agmatine: multifunctional arginine metabolite and magic bullet in clinical neuroscience?
    Jul 26, 2017
    DOI: 10.1042/BCJ20170007


    Agmatine
    , the decarboxylation product of arginine, was largely neglected as an important player in mammalian metabolism until the mid-1990s, when it was re-discovered as an endogenous ligand of imidazoline and α2-adrenergic receptors. Since then, a wide variety of agmatine-mediated effects have been observed, and consequently agmatine has moved from a wallflower existence into the limelight of clinical neuroscience research. Despite this quantum jump in scientific interest, the understanding of the anabolism and catabolism of this amine is still vague.

    Agmatine metabolism:
    F2.large.jpg

    Synthesis and Thermophysical Characterization of New Biologically Friendly Agmatine-Based Ionic Liquids and Salts by Experimental and Computational Approach
    May 17, 2019
    https://doi.org/10.1021/acssuschemeng.9b01515

    For the first time, the dicationic biological molecule agmatine in the synthesis of three novel ionic liquids, agmatine ibuprofenate, agmatine salicylate, and agmatine nicotinate, as well as of six salts, agmatine citrate, agmatine ascorbate, agmatine glutamate, agmatine m-hydroxybenzoate, agmatine nitrate, and agmatine chloride, was used.
     
  9. OP
    Sativa

    Sativa Member

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    Please be careful with your combinations... i'm contemplating MB mixes, but due to unknown chemical interactions, i'm being very cautious in my combinations... I've got some organic chemistry experience/insight so this... helps!

    Be careful with MB, sodium chlorite etc...
     
  10. OP
    Sativa

    Sativa Member

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    I'm also contemplating making salts (of caffeine; agmatine etc) using Nicotinic acid (aka niacin; vitamin B3)...

    Here is some RP relevant research on Agmatine's metabolic interactions.
    It apparently stimulates the endogenous synthesis of allopregnanolone via activation of the PPAR-α receptor & PGC1α! (paper attached)
    Agmatine seems to have a protective effect on mitochondria and modulates fatty acid metabolism, oxygen consumption & ATP synthesis; also seems to prevent dysfunction of Complex I in renal cortex mitochondria, and indirectly regulates cytochrome c oxidase activity.
    Agmatine diminished incomplete fatty acid oxidation, decreased fat but increased protein mass, increased hepatic ureagenesis and gluconeogesis but decreased glycolysis.


    Agmatine is transported into liver mitochondria by a specific electrophoretic mechanism

    Agmatine transport in liver mitochondria may be of physiological importance as an indirect regulatory system of cytochrome c oxidase activity and as an inducer mechanism of mitochondrial-mediated apoptosis.
    [Agmatine is transported into liver mitochondria by a specific electrophoretic mechanism]


    The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis

    Agmatine, an endogenous metabolite of arginine, selectively suppresses growth in cells with high proliferative kinetics, such as transformed cells, through depletion of intracellular polyamine levels. In the present study, we depleted intracellular polyamine content with agmatine
    to determine if attrition by cell death contributes to the growth-suppressive effects. We did not observe an increase in necrosis, DNA fragmentation, or chromatin condensation in Ha-Ras-transformed NIH-3T3 cells administered agmatine. In response to Ca2+-induced oxidative stress in kidney mitochondrial preparations, agmatine demonstrated attributes of a free radical scavenger by protecting against the oxidation of sulfhydryl groups and decreasing hydrogen peroxide content. The functional outcome was a protective effect against Ca2+
    [The arginine metabolite agmatine protects mitochondrial function and confers resistance to cellular apoptosis]


    Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY5Y cells.

    Agmatine, an endogenous arginine metabolite, has been proposed as a novel neuromodulator that plays protective roles in the CNS in several models of cellular damage. However, the mechanisms involved in these protective effects in neurodegenerative diseases are poorly understood. The present study was undertaken to investigate the effects of agmatine on cell injury induced by rotenone, commonly used in establishing in vivo and in vitro models of Parkinson's disease, in human-derived dopaminergic neuroblastoma cell line (SH-SY5Y). We report that agmatine dose-dependently suppressed rotenone-induced cellular injury through a reduction of oxidative stress. Similar effects were obtained by spermine, suggesting a scavenging effect for these compounds. However, unlike spermine, agmatine also prevented rotenone-induced nuclear factor-κB nuclear translocation and mitochondrial membrane potential dissipation. Furthermore, rotenone-induced increase in apoptotic markers, such as caspase 3 activity, Bax expression and cytochrome c release, was significantly attenuated with agmatine treatment. These findings demonstrate mitochondrial preservation with agmatine in a rotenone model of apoptotic cell death, and that the neuroprotective action of agmatine appears because of suppressing apoptotic signalling mechanisms. Thus, agmatine may have therapeutic potential in the treatment of Parkinson's disease by protecting dopaminergic neuron
    [Agmatine effects on mitochondrial membrane potential and NF-κB activation protect against rotenone-induced cell damage in human neuronal-like SH-SY... - PubMed - NCBI]


    Different behavior of agmatine in liver mitochondria: Inducer of oxidative stress or scavenger of reactive oxygen species?

    Agmatine acts as a competitive inhibitor of nitric oxide synthase (NOS) [4] and induces ornithine decarboxylase antizyme [5] and spermidine/spermine acetyl transferase [6]. In fact, in all species agmatine is metabolized by agmatinase to urea and putrescine [7], suggesting that it is a polyamine precursor. In mammals, agmatine is not only synthesized “in situ” by ADC but is also taken up by exogenous sources and transported to several organs, in particular the liver, by an energy-dependent mechanism [8]. It has been reported that, in rat hepatocytes, increased agmatine concentration, by provoking polyamine depletion, promotes apoptosis by increasing caspase-3 activity. This occurs through mitochondrial swelling and release of cytochrome c[9]. Agmatine has also been found in neuronal mitochondria[10], and its metabolic enzymes, ADC and agmatinase, have also been recognized in mitochondria [11], [12], [13], as well as the imidazoline receptor, I2, which binds agmatine although its function is still unknown [14]. Very recently it has also been found that agmatine is transported into liver mitochondria by an energy-dependent mechanism, exhibiting strict electrophoretic behavior and requiring high membrane potentialΨ) in order to operate [15].

    The transport of agmatine in RLM accounts for its up-regulation in ureagenesis, demonstrated in perfused liver [16], coupled with stimulation of β-oxidation [17]. Indeed, agmatine is also able to prevent dysfunction of Complex I in renal cortex mitochondria [18], most probably by phosphorylating the AQDQ subunit of the complex [19]. It has been proposed that these findings may have important implications for the prevention of mitochondrial diseases related to faulty Complex I [18].

    All these observations, revealing close relationships between this amine and mitochondria, taken together with previous reports on interactions among biogenic amines and mitochondria, particularly at the level of oxygen consumption and ATP synthesis...
    [Different behavior of agmatine in liver mitochondria: Inducer of oxidative stress or scavenger of reactive oxygen species? - ScienceDirect]


    Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice

    ...Atherosclerosis is an inflammatory disease in which dysfunction of mitochondria play an important role, and disorders of lipid management intensify this process. Agmatine, an endogenous polyamine formed by decarboxylation of arginine, exerts a protective effect on mitochondria and modulates fatty acid metabolism.
    [Anti-Atherosclerotic Action of Agmatine in ApoE-Knockout Mice]


    The molecular and metabolic influence of long-term Agmatine consumption

    Subsequently, AGM induced a widespread impact on gene expression and metabolic profiling, including: (a) activation of peroxisomal proliferator-activated receptor-α (PPARα), and its coactivator PGC1α; (b) increased expression of PPARγ and genes regulating thermogenesis, gluconeogenesis, and carnitine (Car) biosynthesis and transport. The changes in gene expression were coupled with improved tissue and systemic levels of Car and short chain AcylCar, increased βoxidation and diminished incomplete fatty acid oxidation, decreased fat but increased protein mass, increased hepatic ureagenesis and gluconeogesis but decreased glycolysis. These metabolic changes were coupled with reduced weight gain and a curtailment of the hormonal and metabolic derangements associated with HFD-induced obesity. The findings suggest that AGM elevated the synthesis and level of cAMP, thereby mimicking the effects of caloric restriction with respect to metabolic reprogramming.

    [Attachment: https://raypeatforum.com/community/attachments/metabolic-influence-of-agmatine-pdf.14186/]
     

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  11. OP
    Sativa

    Sativa Member

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    Further insight into methylglyoxal, thanks to Travis.

     
  12. OP
    Sativa

    Sativa Member

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    The benzoate & succinate forms of Caffeine/Agmatine/etc might be interesting, especially since both benzoic & succinic acids have useful & relevant 'peaty' pro-metabolic properties. Other bases such as Magnesium & Calcium could be used...eg Mg Benzoate, Ca Succinate etc

    Of course, it could always be simpler to take these things separately ... but I have a sense of adventure, and experimentation.

     
  13. OP
    Sativa

    Sativa Member

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    Malic acid, forming the malate salt, could be an interesting ingredient. It's a key player in the mitochondrial synthesis of ATP.
     
  14. OP
    Sativa

    Sativa Member

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    More on succinic acids pro-metabolic properties + insight on proper dose quantities & frequency, thanks haidut!

    Also sweet insight into Sodium Acetate, which apparently.boosts internal CO² production... + iirc, Na Acetate
    binds to phosphate; so a good way of reducing P absorption!



    Insight on acetic acid (acetate), in the context of 'acetate salts' eg Calcium acetate, Sodium acetate, magnesium acetate, caffeine acetate etc...
     
  15. OP
    Sativa

    Sativa Member

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    Insight on alkaline mineral [Potassium bicarbonate salt] intake; contrasted with Sodium intake(Na:K ratio), KHCO³ reduces calcium loss/excretion, K promotes insulin secretion (thanks @Amazoniac)
     
  16. OP
    Sativa

    Sativa Member

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    More in-depth insight to Potassium:Sodium ratio:
     
  17. OP
    Sativa

    Sativa Member

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    I've just realised I've mixed up Sodium acetate with Calcium acetate!
    CaAcetate is used for binding & removing excess phosphate!
    One DIY method involves putting egg shells in vinegar, and waiting till the fizzing stops.
    I intend to powder my egg shells using a coffee grinder, then make various Calcium salts by mixing the powder with an acid... eg Salicylic, acetic, succinic etc.


    As a general overall summary so far, theres easy DIY salts for:
    • Increasing internal CO² levels
    • Binding & removing Phosphate
    • Reducing Calcium excretion
    • Enhancing ATP production/cycle
    • Improving aspirin/salicylic acid absorption/reducing GI irritation
     
  18. OP
    Sativa

    Sativa Member

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    Here's the entry for different salts based on salicylate/succinate as found in -
    "Merck's 1896 index : an encyclopedia for the physician and the pharmacist stating the and synonyms ... of the chemicals and drugs used in medicine, in chemistry, and in the arts"
     
  19. OP
    Sativa

    Sativa Member

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    More from Merck's 1896 index - acetate & benzoate salts...

     
  20. OP
    Sativa

    Sativa Member

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    An additional strategy to reducing phosphate (and PTH) levels, is to supplement with vitamin B3 aka naicin/niacinamide.

    High phosphate levels, alongside low Calcium, results in increased release of PTH, which directly increases cortisol.

    Haidut has mentioned that 1g niacinamide (also niacin) daily lowered both phosphate & PTH (parathyroid hormone).
    PTH
    & excess phosphate act as powerful suppressors of metabolism.
    I've already mentioned 2 OTC salts with relevant properties re Ca:P balance:
    • Calcium acetate - binds & removes Phosphate
    • Potassium bicarbonate reduces Calcium excretion aka loss
     
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