White WIllow - Salix alba - Vegetable Aspirin

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POLYPHARMACEUTICAL CHEMISTRY - FULL SPECTRUM - ENTOURAGE EFFECT

One plant species which provides a shining example of an inherent naturally occurring polypharmaceutical effect which occurs both within the single plant species and when the plant species is used in complex with another, is the wonderful Salix alba, our original inspiration for aspirin, which some literature has even hilariously and perhaps preposterously referred to Willow Tree as the “vegetable aspirin” (2). Firstly, it had been assumed hitherto in the scientific culture that the efficacy of orally delivered aqueous Willow Bark extracts was purely a result of salicin and its metabolic derivatives, however, it was shown in clinical trials and pharmacological studies that “the fraction of total salicin [in aqueous willow bark extract] cannot satisfactorily explain the clinical efficacy of willow bark. In addition, salicins and their metabolites lack the acetylating potential of ASA and must therefore possess a different mechanism of action.” (3) Experimental models on fractions of aqueous Willow bark extract were all tested and all results pointed to the relevant contributions of the polyphenolic and flavonoid profile as significant players in the efficacy of Willow Bark aqueous extracts. It was concluded that “The single compounds or their combinations responsible for the [medicinal] effect [of aqueosus Willow Bark extract treatment] remain to be elucidated” (3).

What is Polypharmacy?

Well to put it succinctly, the polypharmacy is simply another way of expressing the Aristotelian axiom that: "The whole is greater than the sum of its parts". Polypharmacy is a complex phenomenon that often is objectively seen simply as the interaction of two or more drugs on a system. Subjectively, I believe it is a misunderstood anomaly within western medicine, yet a nearly inseparable aspect of eastern and traditional medicines like Ayurveda and Alchemy.  It is surrounded by other key misnomers in popular plant medicine culture such as “entourage effect” and “matrix effect”. What these names attempt to define are the typically unexpected consequences of chemical, pharmacological, and social systems when two or more integers (chemical compounds in our case) are participating in an exchange of energy and information (having a chemical or pharmacological reaction) together. Chemically, this means when two atoms or compounds create an effect in reality which is significantly different from the effect of either individual substance. Polypharmacy is often considered as an unintended side effect when mixtures of compounds have reactions together or upon another system. However, in non-materialist cultures, these affects are often taken advantage of in the form of whole plant material based medicines and remedies composed from multiple plants, thus typically constituting possibly thousands of different compounds.

An entourage effect can be considered a cult like sentiment in some plant medicine cultures that states plant medicines and preparations which are constituted from a more complete spectrum of plant constituents, have a sort of heightened phenomenologically obvious experiential effect than do chemical isolates or partitions of the same plant species. This idea suggests that a plants concert of bioactive principles have an inherent synergy that evolved them to be causally positively negentropically related to the human being. This is in contrast to the notion that a plants assortment of active principles have no inherent synergy, relationship or inter-connection to the human. A plant through this perspective is often reduced down via the perspective suggesting that a plants only inherent functions lie in the evolutionary need to multiply and adapt to its ecological pressures. This suggests that the function of a plant medicine may only be understood by analyzing its individuated particle-based constituents. I would like to take the opportunity to explain my theory on where this rift in perspective has come from and to support evidence for the hypothesis that medicinal plants have coevolved with humans to exhibit a collective chemical synergy that is far greater than any one of its individual parts.

Historical Philosophy

This is actually a split in perspective that goes back hundreds of years and is deeply rooted to the foundational scientific paradigms put forth by the forefathers of this institution. That perspective is that one put forth by Galileo Galilee himself who suggested the universe operates like a big mechanical clock. The mechanical universe he called it. That out there in the physical reality, the face of the big clock, there is a manifestation of form and function that is physically causally linked by underlying operations found within its physical constitution. So thus, any effect perceived in reality can always be explained by the interaction of its various parts. This idea greatly inspired Isaac Newton who distilled this concept down to the first law of Newtonian mechanics, which states Objects in motion tend to stay in motion, and objects at rest tend to stay at rest unless an outside force acts upon them. This kind of thinking birthed the materialist, reductionist, deterministic empiricist viewpoint that ultimate knowledge can be attained from enquiry to the physical nature of objects interacting with each other.

This theory has persisted to this day due to its exemplary explanatory power, however with simple experimentation, Newton actually falsified some his own precepts he set out with. Newton wrote in letters to his peers “you sometimes speak of gravity as essential & inherent to matter: pray do not ascribe that notion to me, for ye cause of gravity is what I do not pretend to know, & therefore would take more time to consider of it.” He left this planet with the mystery still wide open, “Gravity must be caused by an agent [acting] consta[ntl]y according to certain laws, but whether this agent be material or immaterial is a question I have left to the consideration of my readers.” (1) And again, centuries later modern physicists the likes of Einstein, Heisenberg, Bohr, Bohm, Shroedinger, John Wheeler and many others came to the same conclusions with quantum physics. Seemingly non-physical forces have causal engagement with physical systems. Quantum entanglement and the double-slit experiments led to Einsteins famous saying of that “spooky action at a distance”. Spooky because it breaks Newtons first law of physics. However, the continual attachment to the fruits of this perspective led to the commonly held belief that the best technical explanations we have for reality, including its plant and human constituents, are atomic, particle, fundamentally material conceptions and interactions. However experimentation indicates otherwise.

I believe that this ‘spooky action in the distance’ is that root cause of the polypharmaceutical effect. Perhaps more aptly said, the inherent relationships between man and nature. Polypharmacy, entourage, matrix effects, all suggests that matters holistic properties and interrelationship with other matters cannot be fully comprehended when analyzed from its individual constituents. Matter/s must be taken as a whole in relativity to its parts before coming to understanding any organic composites’ natural interaction with another organic composites. This is why I feel polypharmacy is considered some kind of unpredictable anomalous effect rather than an intended consequence of calculated combinations of compounds and collections of compounds that are inherently interrelated and synergetic. Due to this we often are led to both negative and anomalous effects from certain plant materials, among other physical paradoxes, but likewise unexpected but pleasant discoveries of apparent synchronicities within the natural world when these synergies are wandered upon. That’s my theory anyways and Im sticking to it!

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Medicinal Chemistry

Salix alba, commonly known as the White Willow, is a tree species that has been used for centuries for its medicinal properties. The bark of the white willow contains a full spectrum of medicinal compounds, including salicylic acid which is a natural compound that has been shown to have a range of beneficial effects on human health, flavonids, tannins, polyphenols which carry therpeutic affects and essential nutritional minerals which are vital for long term health, longevity, and alchemical immortality.

One of the most significant benefits of salicylic acid in the white willow bark is its ability to reduce pain and inflammation. This compound works by inhibiting the production of prostaglandins, which are responsible for causing inflammation in the body. As a result, the use of white willow bark extract has been shown to be effective in relieving a range of conditions such as headaches, menstrual cramps, and osteoarthritis.

The Relevant Chemicals in Aqueous Willow Bark Extract:

Salicylic acid, Polyphenols and flavonoids – One of the simplest medicinal compounds, and an alcohol group awAy from another good compound benzoic acid, salicylic acid is composed of a phenolic benzene ring with a carboxyl group on it. Interestingly enough, a benzene ring alone is carcinogenic, but the simple alcohol carboxyl addition provides not only bioactivity and availability, but a wide range of pharmacological effects from skin and hair care to various pain treatments (3). Willow bark contains up to 20% flavonoids and condensed tannins. “Typical representatives of the flavonoids are glucosides of naringenin, isosalipurpuroside or eriodictyol [4]. Other polyphenols also form a major fraction in aqueous extracts from willow bark: recently the flavan-3-ols catechin, epicatechin, gallocatechin, catechin-3-O-(1- hydroxy-6-oxo-2-cyclohexene-1-carboxylic acid)-ester, the dimeric procyanidins B1, B3 and the trimeric procyanidins epicatechin-(4β8)-catechin-(4α8)-catechin and epicatechin-(4β8)-epicatechin-(4β8)-catechin were isolated from the bark of S. purpurea” (3). All of these compounds are generated via the famous shikimate/phenylpropanoid pathway responsible for polyphenols and flavonoids. Aqueous Willow bark extracts have further known to have a number of therpeutic, medicinal and pharmacologic mechanisms: Inhibition of enzymes of arachidonic acid metabolism in human cells, dose dependent ihibition of gene expression of mediators of inflammation, and the antioxidative potential of polyphenols mediated free radical processes. “Polyphenols such as flavonoids and proanthocyanidins also seem to contribute to effects of willow bark hitherto not used therapeutically, such as antiproliferative and apoptosis-inducing activity in cancer cells” (3).

More research is needed to understand salicyclic acids far reaching pharmacological effects, but we know that one of its key actions is known to inhibit prostaglandin synthesis which is critical in the inflammation response. As the matrix/entourage/polypharmaceutical/Jungian synchronicity/spooky-action-in-the-plants effect would play out, the flavonoid and polyphenolic portion likewise mediate inflammation by a ‘multidirectional’ antioxidizing affects.

All of these compounds are readily identifiable via GC-MS.

It is also worth mentioning the strong synergism between Coffee and Willow Bark aqueous extracts. Proposed mixtures could be used in prophylaxis and oxidatively linked diseases as globally (widely distributed through the body) antioxidizing compounds.  “It has been found that the biologically active compounds contained in the analyzed raw materials interact with each other, thus affecting their activity.”It was noted the thermal stability and hydrophilicity of salicilins further justified its use in coffee. “Obtained results indicate that extracts from bark tested Salixgenotypes as an ingredient in coffee beverages can provide health promoting benefits to the consumers; however, this issue requires further study” (4). I would further like to test the interactions with different teas!

LADMET for Salicylic acid

Liberation – The compound salicin which is the primary constituent of the white willow bark is liberated from the tree when it is extracted from the bark into an aqueous decoction (also known as tea). When this tea is consumed the compound enters the stomach and intestine where it is metabolized through a “glycon hydrolysis and oxidation of the benzyl carbon” reaction. It is then absorbed into the blood stream in its pharmacologically active form, salicylic acid (1)

Metabolism  –  There is further metabolism of salicylic acid in the kidney and liver where it can form an ether or ester bond by conjugation with glycine to form salicyluric acid and salicylacyl glucuronide (1). These compounds are watersoluyble and can be excreted through the urine

Distribution – Once it is metabolized from the stomach it is circulated through the bloodstream and can be delivered to various organs

Therpeutic Index - Therapeutic drug levels for aspirin are 150 to 300 mcg/mL (salicylate) (2)

Toxic Levels - Greater than 300 mcg/mL (2)

LADMET for Flavonoid, Naringinen

Commonly liberated simply through eating, as this is a  flavonoid found in many foodstuffs and medicinal plants, it is poorly absorbed into the gut but has a larger bioavailability orally. The oral bioavailability (sublingual) of naringenin is around 15%, and only low amounts are absorbed in the human gastrointestinal tract due to its low solubility (3)

Absorpton – Naringenin is absorbed through the gut wall from oral administration. Its metabolites are glucurono- and sulfoconjugated derivatives of naringenin. (3)

Metabolism – Little is known about the metabolism of naringinen in humans

Distribution – “Naringin and naringenin are distributed in the lungs, trachea, gastrointestinal tract, liver and kidneys In the intestinal and liver cells. Naringin and naringenin undergo phase I (oxidation or demethylation by cytochrome P450 monooxygenases) and phase II (glucuronidation, sulfation or methylation) metabolism” (3)(4)

Excretion – “Excretion is mainly through urine, and some metabolites are found also in feces.” (4)

Toxicity - naringin concentrations >200 μg/mL are toxic and may lead to cell death (Zhang et al. Citation2009).

Sollubilities in different solvents

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Non-toxic

The use of white willow bark extract is also safe and non-toxic due to the presence of natural salicylic acid. Unlike synthetic salicylic acid, which can cause gastrointestinal irritation and other side effects when used in high doses, the natural form found in white willow bark is gentle on the stomach and liver.

Nutritional Information - Essential Minerals

While the bark of Salix alba (white willow) is primarily known for its medicinal properties, it also contains a number of naturally occurring mineral salts that also have nutritional benefits. Some of the mineral salts that can be found in the bark of Salix alba include:

1. Calcium: This mineral is essential for strong bones and teeth, as well as for proper muscle and nerve function.
2. Magnesium: Magnesium is important for maintaining healthy blood pressure, heart function, and muscle and nerve function.
3. Potassium: Potassium helps regulate fluid balance in the body, as well as nerve and muscle function.
4. Iron: Iron is essential for the production of red blood cells, which carry oxygen throughout the body.
5. Zinc: Zinc is important for immune system function, wound healing, and DNA synthesis.
6. Manganese: Manganese is involved in a number of important bodily processes, including bone formation, wound healing, and metabolism.
7. Phosphorus: Phosphorus is important for the formation of bones and teeth, as well as for energy metabolism and the regulation of cell function.
8. Sodium: Sodium is necessary for proper fluid balance in the body, as well as nerve and muscle function.
9. Copper: Copper is important for the formation of red blood cells, as well as for immune system function and the metabolism of iron.

It is important to note that the exact composition of mineral salts in the bark of Salix alba may vary depending on factors such as soil composition, climate, and the age of the tree. Nonetheless, these mineral salts play an important role in maintaining overall health and wellbeing.

Spagyric plant medicine treates the source of disease becasue they containe a naturally balanced and ratioed deposit of minerals that are readily bioavailable to bring balance back to the essential mineral profile of every human. Click here to learn more about essential minerals.

Synergy

In addition to salicylic acid, the white willow bark contains a full spectrum of medicinal compounds that work synergistically to produce a range of health benefits. These include flavonoids, tannins, and phenolic acids, which have antioxidant and anti-inflammatory properties. These compounds work together to enhance the effectiveness of salicylic acid and provide additional health benefits such as improved cardiovascular health and reduced risk of cancer. Similarly, the presence of nutritional mineral salts catalyze intra tincture reactions which lend to the enhanced bioavailbility of the spectrum of medicinal compounds. These essential mineral salts are further therpeutic as all plants act as natural deposits of macro and micro nutrients which are essential for human metabolic health and are likewise especially retained in spagyric plant medicine. Mineral balance is a fundamental tenet to health and vitality and contributes significantly to the overall medicinal value of spagyric tinctures.

Alchemy

In the doctrine of signatures, plants were believed to have physical characteristics that indicated their potential medicinal uses. Similarly, in the alchemical tradition, plants were associated with specific planetary correspondences based on their physical and metaphysical properties.

The white willow (Salix alba) was traditionally associated with the planet Mars in both the doctrine of signatures and the alchemical tradition. This is because the tree's bark is astringent, bitter, and cooling, which were thought to correspond to Mars' qualities of strength, courage, and discipline. The white willow was often used to treat conditions such as fever, inflammation, and pain, which were also associated with Mars.

In addition to its association with Mars, the white willow was also thought to have lunar correspondences due to its ability to grow in damp, watery environments. Its flexible branches were also associated with the moon's fluid, changeable nature. As a result, the white willow was sometimes used in lunar rituals and associated with the goddess of the moon.

Warning

It is important to note that while white willow bark extract is generally safe and non-toxic, it should still be used with caution and under the guidance of a healthcare professional. It may interact with certain medications, and high doses may cause gastrointestinal upset or other side effects. However, when used appropriately, white willow bark extract can be a safe and effective natural remedy for a range of health conditions.

Salix alba

SOURCES

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2 Arif H, Aggarwal S. Salicylic Acid (Aspirin) [Updated 2022 Jul 11]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK519032/#

3 Bioavailability of the flavanone naringenin and its glycosides in rats ... https://journals.physiology.org/doi/full/10.1152/ajpgi.2000.279.6.g1148 (accessed Apr 30, 2023).

4 Stabrauskiene J, Kopustinskiene DM, Lazauskas R, Bernatoniene J. Naringin and Naringenin: Their Mechanisms of Action and the Potential Anticancer Activities. Biomedicines. 2022 Jul 13;10(7):1686. doi: 10.3390/biomedicines10071686. PMID: 35884991; PMCID: PMC9313440.

Solubilities of Salicylic Acid in Pure Solvents and Binary Mixtures Containing Cosolvent† Hiroyuki Matsuda,*,‡ Kenta Kaburagi,‡ Sho Matsumoto,‡ Kiyofumi Kurihara,‡ Katsumi Tochigi,‡ and Kazuo Tomono§ Department of Materials and Applied Chemistry, Nihon University, 1-8-14 Kanda Surugadai, Chiyoda-ku, Tokyo 101-8308, Japan, and College of Pharmacy, Nihon University, 7-7-7 Narashinodai, Funabashi-shi, Chiba, 274-8555, Japan https://pubchem.ncbi.nlm.nih.gov/compound/Salicylic-Acid#section=Computed-Properties National Center for Biotechnology Information (2023). PubChem Compound Summary for CID 338, Salicylic Acid. Retrieved August 9, 2023 from https://pubchem.ncbi.nlm.nih.gov/compound/Salicylic-Acid.

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(1)   Newton's second letter to Richard Bentley (17 Jan 1692/3). Collected in Four Letters From Isaac Newton to Doctor Bentley, Containing Some Arguments in Proof of a Deity, (1756), 20

(2) NEAGU, M., LUNTRARU, C., BÎRA, A., TOMESCU, J., IONESCU, N., & STAN, R. BIOACTIVE PHENOLIC COMPOUNDS FROM WHITE WILLOW (SALIX ALBA) BARK, LEAVES AND BRANCHES.

(3) Nahrstedt, Adolf, et al. "Willow bark extract: the contribution of polyphenols to the overall effect." WMW Wiener Medizinische Wochenschrift 157.13 (2007): 348-351.

(4) Agata Durak, Urszula Gawlik-Dziki, "The Study of Interactions between Active Compounds of Coffee and Willow (Salix sp.) Bark Water Extract", BioMed Research International, vol. 2014, Article ID 386953, 11 pages, 2014. https://doi.org/10.1155/2014/386953

Agata Durak, Urszula Gawlik-Dziki, "The Study of Interactions between Active Compounds of Coffee and Willow (Salix sp.) Bark Water Extract", BioMed Research International, vol. 2014, Article ID 386953, 11 pages, 2014. https://doi.org/10.1155/2014/386953

Trissel’s Stability of Compounded Formulations, 6th Edition  Mar 2018 Salicylic Acid – Sodium Phenylbutyrate https://doi.org/10.21019/9781582122960.sa

Nahrstedt, Adolf, et al. "Willow bark extract: the contribution of polyphenols to the overall effect." WMW Wiener Medizinische Wochenschrift 157.13 (2007): 348-351.

U.P.B. Sci. Bull., Series B, Vol. 83, Iss. 3, 2021 ISSN 1454-2331 BIOACTIVE PHENOLIC COMPOUNDS FROM WHITE WILLOW (SALIX ALBA) BARK, LEAVES AND BRANCHE Miruna NEAGU1, Cristina LUNTRARU2, Adriana BÎRA (POPESCU)3, Justinian TOMESCU4, Natalița IONESCU (BORDEI)5, Raluca STAN6*

Efficacy and tolerability of a standardized willow bark extract in patients with osteoarthritis: randomized placebo-controlled, double blind clinical trial^† B Schmid, R Lüdtke, H-K Selbmann, I Kötter, B Tschirdewahn, W Schaffner, L Heide First published: 08 June 2001 https://doi.org/10.1002/ptr.98 Citations: 89 ^† First published in German language in Zeitschrift für Rheumatologie 2000; 59: 314-320.

Characteristics of Hot Water Extracts from the Bark of Cultivated Willow (Salix sp.) Jinze DouJinze Dou Department of Bioproducts and Biosystems, School of Chemical Engineering, Aalto University, Vuorimiehentie 1, P.O. Box 16300, Aalto FI-00076 , FinlandMore by Jinze DouWenyang Xu, ari J. Koivisto, Justin K. Mobley, Dharshana Padmakshan, Martin Kögler, Chunlin Xu, Stefan Willför, John Ralph, and Tapani Vuorinen* ACS Sustainable Chem. Eng. 2018, 6, 4, 5566–5573 Publication Date:February 28, 2018https://doi.org/10.1021/acssuschemeng.8b00498 Copyright © 2018 American Chemical Society

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Srivastava, J. K.; Shankar, E.; Gupta, S. Chamomile: A herbal medicine of the past with bright future. Molecular Medicine Reports 2010, 3 (6), 895-901.

Gagnier, J. J.; van Tulder, M.; Berman, B.; Bombardier, C. Herbal medicine for low back pain: a Cochrane review. Spine 2007, 32 (1), 82-92.

Schmid, B.; Lüdtke, R.; Selbmann, H. K.; Kötter, I.; Tschirdewahn, B.; Schaffner, W.; Heide, L. Anwendung und Verträglichkeit von Weidenrindenextrakt bei degenerativen Erkrankungen des Bewegungsapparates. Rehabilitation (Stuttg) 2000, 39 (2), 93-102.

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