Introduction

Peripheral neuropathy is a common disorder. Over the age of 55, neurologists confirmed a prevalence of 8% (1) and the prevalence increases with age. Diabetes mellitus, a common cause of neuropathy, has a prevalence of neuropathy of 15%, 20 years after diagnosis (2). In addition to a symmetric polyneuropathy, peripheral nerve disorders include single and multiple polyneuropathies and radiculopathies. Numerous causes of neuropathy have been identified although a significant percentage are idiopathic (of unknown cause). Common causes include diabetes and alcoholism with genetics, autoimmune and iatrogenic (caused by medicine or surgery) being other causes. Underlying mechanisms of neuropathy include free radicals (3), inflammation (4) and excess glutamate neurotransmission (5).

Application: Nerve Balm, from Supplement Creams, is a unique topical cream, professionally formulated from herbs and nutrients to reduce neuropathic pain and promote healing of the involved nerves. It is a rich cream and a light layer over the involved region may be all that is required. Application of too thick a layer of cream might cause a temporary burning sensation.

Product Details: This product has not been evaluated by the FDA and there is no intention to diagnose, treat or cure any specific medical diagnosis. Over the last five years, patients with nerve entrapments, back pain with radiating pain, shingles, as well as joint arthritis have also enjoyed relief of pain using Enhanced Nerve Balm.

A unique feature of Nerve Balm is the inclusion of multiple constituents to address the mechanisms of pain in neuropathy. In regards to glutaminergic transmission, magnesium and taurine, in Enhanced Nerve Balm, both diminish the role of glutamate in pain transmission. GABA (gamma amino butyric acid) is the main inhibitory neurotransmitter in the nervous system and balances the excitatory effects of glutamate. The inclusion of GABA in Enhanced Nerve Balm helps reduce the excitatory effects of glutamate in pain transmission. In addition, vinpocetine, in Enhanced Nerve Balm, is known to block the NaV1.8 sodium channel of neuronal membranes. This particular sodium channel is important for neuronal potential transmission in pain fibers. By blocking the channel, inhibition of pain transmission ensues. As described below, the essential oils have constituents with various analgesic mechanisms. Shankhpushpi also has interesting analgesic properties.  The use of Shankhpushpi (convolvulus pluricaulis) in a topical cream is another unique feature of Nerve Balm. Traditionally, Shankpushpi is used orally as a nootropic.

In regards to the inflammatory and free radical components of peripheral neuropathy, Nerve Balm provides multiple constituents with anti-inflammatory and anti-oxidant activity. Alpha lipoic acid, in addition to being considered the “ideal” endogenous anti-oxidant (6a), has a definite anti-inflammatory effect (6 b). As discussed below, all four essential oils have both analgesic and anti-inflammatory properties. Aloe has similar analgesic and anti-inflammatory properties. Bacopa and sesame seed oil have interesting analgesic properties.

Another unique feature of Nerve Balm is the combination of St John’s Wort and Lion’s mane ( western nervines), and Bacopa and Shankpushpi ( Ayurvedic nervines) into one topical cream. The individual properties of these plants are discussed below.

Finally, the inclusion of Shankhpushpi (convolvulus pluricaulis) in a topical cream is unique. Shankhpushpi is an oral Ayurvedic nootropic. Its benefit in a topical cream for neuropathy was based on its clinical benefits noted by people in the clinical trial that helped the formulation of Nerve Balm.

1.     Martyn CN and Hughes RAC Epidemiology of peripheral neuropathy. Journal of Neurology, Neurosurgery, and Psychiatry 1997;62:310-318

2.     Ibid

3.     Tal M A novel antioxidant alleviates heat hyperalgesia in rats with an experimental painful peripheral neuropathy. Neuroreport. 1996 May 31;7(8):1382-4

4.     Somer C and Kress M Recent findings on how proinflammatory cytokines cause pain: peripheral mechanisms in inflammatory and neuropathic hyperalgesia. Neurosc Lett. 2004 May 6;361(1-3):184-7

5.     Osikowicz M et al The glutaminergic system as a target for neuropathic pain relief. Exp Physiol, 2013 Feb;98(2):372-84

6a   Packer L et al Neuroprotection by the metabolic antioxidant alpha-lipoic acid. Free Radic Biol Med. 1997;22(1-2):359-78

6b  Odabasogle F et al Alpha-lipoic acid had anti-inflammatory and anti-oxidative    properties: an experimental study in rats with carrageenan-induced acute and cotton pellet-induced chronic inflammations. Br J Nutr. 2011 Jan;105(1) Jan;105(1):31-43.I

Ingredient Details of Supplementcreams Nerve Balm

Magnesium
Magnesium is an essential metal for biological health. Over 300 human enzymes require magnesium to function. One reason that magnesium is so important is that by “chelating” to an organic molecule, it helps determine the overall shape, or tertiary folding, of the molecule. If a molecule does not fold properly, particularly an enzyme, then it loses it functional capacity. For example, an active site of an enzyme needs to be exposed and conform properly to the “substrate” of the enzyme.  This only occurs with proper folding of the protein.

48% of Americans consume less than the established required daily intake amount of Magnesium (10). This same reference notes that low blood levels and low nutritional intake of magnesium is associated with Type 2 diabetes, metabolic syndrome, elevated C-reactive protein, hypertension, atherosclerotic vascular disease, sudden cardiac death, osteoporosis, migraine headache, asthma and colon cancer.

The importance of magnesium in Nerve Balm is its role in blocking a particular neurotransmitter receptor, the NMDA receptor for the excitatory neurotransmitter, glutamate. Glutamate is an amino acid in the body. In addition to its incorporation into proteins, glutamate is the most abundant excitatory neurotransmitter in the nervous system. A simple definition of a neurotransmitter is a chemical that is secreted by one nerve cell to either stimulate or inhibit another nerve cell or muscle or glandular cell. The chemical is released by one nerve cell into a space called the synapse; it then crosses the synapse to act on a post-synaptic surface. There are numerous neurotransmitters, but for our purposes, we will focus on two main ones, glutamate and GABA. Glutamate is the most common neurotransmitter in the brain, with GABA a close second occurring in 20-30% of synapses. The balance between glutamate and GABA is very important.  An excess of glutamate increases the risk of a seizure in epileptics, increased pain in pain disorders and even cell death in a process called excitotoxicity.  It is also of interest that glutamate is metabolized to GABA in one enzymatic step.

There are two classes of glutamate receptors, ionotropic and metabotropic. In terms of magnesium, the NMDA ionotropic receptor is the one affected by magnesium. NMDA receptors are located in the brain, spinal cord and peripheral nerves. In terms of pain, the NMDA receptors in the peripheral nerves and the spinal cord are most important for the action of Enhanced Nerve Balm. The magnesium appears to bind inside the ion channel associated with the NMDA receptor. The positive magnesium ion is held in place by electrostatic attraction to the negatively charged interior of the neuron. If the neuron “depolarizes”, reducing the voltage across the nerve cell membrane, the magnesium ion dislodges and the ion pore is open. From a quantum point of view, the ion channel can assume an open or closed mode. The magnesium increases the likelihood of a closed mode, stopping the influx of calcium into the cell. The more magnesium in the body, the less likely it is that the NMDA receptor will respond to glutamate. The influx of calcium through a presynaptic NMDA receptor ion pore, allows for release of a neurotransmitter to excite the postsynaptic neuron.  Magnesium then, can decrease glutaminergic transmission, thereby decreasing its role in pain transmission.

Taurine
Taurine is an amino acid although it does not have the carboxyl acidic group like the amino acids incorporated into proteins. It is one of the most abundant amino acids in the body and, surprisingly, measures as 0.1 percent of the total human body weight. It is found in multiple organs in the body including the nervous system. It has multiple functions in the central nervous system, including cytoprotection (protection of cells in the nervous system) (11).

Taurine has been shown to have multiple functions in the human body. These functions include modulation of ion movement, conjugation of bile acids, osmoregulation, neurotransmission and as a neuroprotectant. Taurine also functions as an antioxidant, analgesic, calcium modulator and vasodilator. In regards to its role as a neurotransmitter, it appears to elicit hyperpolarization of neuronal cell membranes (12). This is of interest in that glutamate, as an excitatory neurotransmitter would elicit depolarization. In particular, it is thought that taurine prevents glutamate induced membrane depolarization by opening chloride channels in the cell membrane (13).

A number of studies are reported on the beneficial effect of taurine in diabetic neuropathy. Some of the findings may have application in non-diabetic neuropathy. Taurine is known to counteract oxidative stress in multiple tissues in experimental diabetic rats. It has also been shown that taurine improves blood flow to nerves as well as increasing nerve conduction velocities in diabetic rats. A 2001 study at the University of Michigan revealed that Taurine, in addition to reducing oxidative stress, also improved levels of nerve growth factor (NGF) in diabetic peripheral nerves. It is known that NGF declines in diabetic peripheral nerves (14).

A Japanese study in 2011 studied the mechanism of taurine’s known benefit of reducing neuropathic pain. The study was performed on rats that suffered a constriction injury to their sciatic nerve. They used various methods to determine the antinociceptive effect of taurine injected into the cerebrospinal fluid. The taurine reduced the level of pain and the mechanism appeared related to increased levels of glycine neurotransmission (15). Glycine is know to be an inhibitory neurotransmitter and in this case, inhibited the transmission of the pain stimulus.

Vinpocetine 
Vinpocetine is a compound derived from an alkaloid found in the lesser periwinkle plant that goes by the name myrtle or creeping myrtle in the US.  It is a pentacyclic compound with a side chain. The inclusion of vinpocetine relates to its property of blocking sodium channels in neuronal membranes.

Neuronal sodium channels are openings in the membrane bound by large transmembrane proteins. They open and close depending on the transmembrane potential. As stated in the article by M Devor from Hebrew University in Jerusalem “They are critical determinants of the electrical excitability of sensory neurons and play a key role in pain sensation by controlling afferent impulse discharge” (16). The author goes on to state that injury or disease causes a remodeling of the nerves including increased excitability due to changes in the sodium channels. The author goes on to state “The resulting excess discharge constitutes a primary neuropathic pain signal…Membrane-stabilizing Na+ channel ligands suppress neuropathic pain by selectively reducing membrane resonance in injured afferents and hence ectopic hyperexcitability”. In other words, compounds that bind to the sodium channel can suppress neuropathic pain. It has long been known that the sodium channels are involved in the transmission of nerve impulses. Altered anatomy of sodium channels in neuropathy can cause hyperexcitability of the sensory neuronal membrane, hence the experience of pain.

It is well established that vinpocetine blocks voltage-dependent neuronal sodium channels. In fact, a Hungarian study reported in 1995 shows that the hyperpolarizing effect of vinpocetine on sodium channels was as strong as the effect of Dilantin(17). This property of Dilantin contributes to its anticonvulsant effect. It is also of interest that of the multiple subtypes of sodium channels, the NaV1.8 subtype is found selectively on peripheral afferent nerves.  A 2003 study from the Schering-Plough Research Institute found that vinpocetine can block this particular sodium channel subtype. The authors conclude “In summary, the present data demonstrate that vinpocetine is capable of blocking NaV1.8 sodium channel activity and suggest a potential additional utility in various sensory abnormalities arising from abnormal peripheral nerve activity.”(18)

Essential oils
Essential oils are highly concentrated aromatic oils distilled from plants.  They have been used throughout history with the first recorded documentation in the 1100’s by Islamic writers in Spain.  There has recently been a resurgence of interest in essential oils (aroma therapy) with oils be taken orally, through the breath with a vaporizer and topically.

In an interesting online article by David Stewart, Ph.D., R.A. he notes that the molecules in essential oils are small and lipid soluble, therefore crossing the blood-brain barrier (19). He goes on to describe the extreme concentration noting that one drop contains 40 million-trillion molecules. This is 40,000 times the number of cells in the human body. He goes on to note that since a single molecule can affect a receptor site, inhalation of a small amount of an oil’s aroma may have a significant effect on our body and how we feel.

The major chemical constituents of essential oils can be divided into two groups, hydrocarbons called terpenes, and the oxygenated compounds, which are mainly esters, aldehydes, ketones, alcohols, phenols, and oxides. The basic unit of the terpenes is an isoprene unit consisting of 5 carbons with two double bonds. It is a volatile hydrocarbon and it is estimated that the world’s vegetation emits 600 million metric tons of isoprene into the atmosphere accounting for approximately 1/3 of all volatile hydrocarbons emitted into the atmosphere (20). The next step up are phenylpropanoids consisting of one isoprene unit with a benzene ring and other variable changes to the molecule such as an ammonia group attached to the isoprene unit. Examples of phenylpropanoids include phenylalanine, tyrosine, cinnamic acid, safrole and trans-resveratrol. Two isoprene groups make up the monoterpenes and three the sesquiterpenes. Examples of monoterpenes include camphor, thymol, eucalyptol, linalool and menthol. Examples of sesquiterpenes include farnesene, germacrene, norpatchulenol and thujopsene. There are dozens of phenylpropanoids, about 2000 monoterpenes, and over 10,000 kinds of sesquiterpenes (21). An interesting study from Brazil examined plant constituents with analgesic properties. Of the 43 “bioactive” compounds selected, 62.8 percent were monoterpenes, 18.6 percent were sesquiterpenes and 18.6 percent were other types of compounds (22).  There is research interest in these compounds for their analgesic properties.

 Peppermint essential oil
Peppermint oil contains the monoterpenes menthol, methane, menthofuran as well as menthyl acetate, the monoterpene oxide 1-8 cineole.  The monoterpene oxide 1,8 cineole (cineole) was studied for its analgesic properties in a Brazilian study in rats. It showed analgesic properties that were not mediated through the mu-opioid receptor. The abstract also notes other studies regarding the inhibitory effect of cineole on the formation of prostaglandins and cytokines suggesting an anti-inflammatory effect (23).

An Italian study reports on the analgesic properties of menthol. Of interest, they note that the cooling effect of topical menthol relates to stimulation of “cold” receptors by inhibiting calcium current in neuronal membranes. It is well known that calcium channel blockers have analgesic properties.  In a mouse model, their research demonstrated an analgesic effect of menthol that appeared to be mediated by selective activation of kappa-opioid receptors (24).

Another interesting European study examined the transneuronal membrane currents at the GABA and glycine receptors, known inhibitory receptors in the nervous system. Menthol and related compounds increased the currents at these receptors. They conclude by saying “This study reveals a novel neuroactive role for menthol as a stereoselective modulator of inhibitory ligand-gated channels” (25).

A British study in 2002 reported on the use of peppermint oil in post-herpetic neuralgia. A 76 year old woman’s post-herpetic pain was resistant to standard therapies.  She was instructed to apply a 10% menthol peppermint oil to the involved skin which resulted in “almost immediate” improvement in pain that lasted 4-6 hours. After 2 months she continued to enjoy analgesia from the oil with only a minor side effect (26).

Rosemary essential oil
Rosemary essential oil has  22 components by gas chromatography. There are two major ones, 1,8-Cineole which is a monoterpene oxide and alpha-pinene, a monoterpene(27).  Of interest is that this latter study revealed significant anti-bacterial and anti-fungal activity.  A Brazilian paper noted above, notes that 1,8-Cineole  has anti-inflammatory activity in rats, including suppression of prostaglandin and cytokine formation, and analgesic activity in mice. A mu-opioid receptor antagonist naloxone did not reduce the anti-nociceptive activity suggesting an alternative pathway for its anti-nociceptive property. They conclude by stating that the findings “…provide additional evidence for its potential beneficial use in therapy as an anti-inflammatory and analgesic agent” (28). A Turkish study in 2008 studied the antinociceptive activity of alpha-pinene in mice. Using various standard tests for nociception in animals, they found significant anti-nociceptive activity of alpha-pinene. The effect was not as strong as morphine but lasted longer (29).

Lavender essential oil
Lavender essential has multiple monoterpenoids and sesquiterpenoids. The predominant terpenes are linalool and linalyl acetate. Linalyl acetate is the acetate ester of linalool. Linalool is a monoterpene alcohol. Multiple papers report the anti-nociceptive properties of linalool.  A 2004 article from Italy discusses that the “anti-nociceptive effect of linalool has been attributed to stimulation of the cholinergic, opioidergic and dopaminergic systems, to its local anaesthetic activity and to the blockade of N-methyl-D-aspartate (NMDA) receptors.” Using a rat model, the investigators found that (-)-linalool decreased hyperalgesia induced by injection of carrageenan, L-glutamate and prostaglandin E(2) into a paw of a rat. They conclude by saying “The efficacy of (-)-linalool in decreasing the hyperalgesia induced by carrageenan, L-glutamate and prostaglandin E(2) suggests that this compound might be useful in pain conditions sustained by the development of neuronal sensitization.” It should be noted that hyperalgesia is an increased sensitivity to painful stimuli and antinociception is a generally reduced sensitivity to pain (30). It should be noted that there are two prior papers by these same authors on the anti-inflammatory and anti-nociceptive properties of linalool and linalyl acetate.

An interesting Brazilian study in 2010 studied (-)-linalool in adult Swiss mice after injection of an inflammatory agent into their paws or after partial sciatic nerve ligation. They then tested for tactile and thermal hypersensitivity. They found that (-)-linalool reduced “mechanical” hypersensitivity both acutely and after 10 days of treatment with (-)-linalool. They also report that (-)-linalool significantly reduced paw edema with the injection of Freund’s adjuvant (31).

Aloe Vera
Aloe Vera is a succulent, perennial plant that naturally grows in extremely dry and poor soils. It will also grow in many different types of soil, from sandy to moderately fertile loam, as long as they have good drainage. It tends to grow in hot, dry climates. It is found in Africa, Asia, Europe, and the Americas. Aloe vera belongs to the genus aloe, which contains over 500 species of flowering succulent plants. Vera means true and aloe vera has a number of identical Latin binomials including A. barbadensis Miller. Aloe indica Royle, Aloe perfoliata L. var. vera and A. vulgaris. The plant contains 19 of the 20 known amino acids, which are essential for humans along with 12 anthraquinones, enzymes, hormones, lignans, salicylic acid, saponins and sterols. It has a long history of use in Chinese and ayurvedic medicine and is considered by some authors one of the most commonly used medicinal plants in history (32). Some of its medicinal uses include use as a topical anaesthetic, treatment for burns, prevention of skin complications from radiotherapy, skin moisturizer, anti-inflammatory for cold sores, eczema and pruritus, diabetes and ulcerative colitis. Traditional uses include benefits in the treatment of tumors, arthritis, and diabetes, enhancing immunity and lowering cholesterol levels. Components of aloe vera are metabolized by the cytochrome p450 system 3A4 and CYP2D6. Oral aloe vera could potentially affect the metabolism of drugs that are metabolized by these specific P450 pathways. Aloe vera is commonly used in cosmetics, skin care products well as beverages and food products. Of note is that the skin absorbs Aloe vera up to four times faster than water. Studies suggest that aloe vera promotes opening of the pores of the skin. Additionally, numerous constituents within Aloe vera have demonstrated enhancement of immune system functioning including the ability to stimulate macrophages, cells in the blood that engulfs cellular debris, foreign substances and essentially anything it detects to be foreign to the bodies healthy functioning.

The aloe vera leaf is processed in two ways. The inner gel can be extracted for use or the decolorized whole leaf can be ground up followed by removal of the “latex”. The latex exists between the outer rind and the inner gel and contains bitter phenolic compounds including some anthraquinones, anthrone and anthraquinone glycosides. Anthraquinone is a type of quinone. Quinones are polycyclic benzene rings with an even number of oxygen or other types of substitutions for the hydrogen attached to the carbons in the benzene ring. The double bond to the oxygen results in the loss of the classic benzene alternating double bond structure. An anthraquinone glycoside is an anthraquinone with an attached sugar compound. The anthraquinone glycoside in senna is responsible for its laxative effect. The major anthraquinone glycoside in aloe vera is aloin A found in the latex. In May 2002, the U.S. Food and Drug Administration (FDA) issued a ruling regarding the use of aloin with the result that aloin-containing products are no longer available in over-the-counter drug products in the United States, because they may be carcinogenic and more data is required to prove otherwise. Aloe vera for medicinal use cannot contain aloin.  

Topical aloe vera has antinociceptive (pain blocking), anti-inflammatory and antioxidant properties, which make it an important plant to consider for topical use for peripheral neuropathic pain. The following is a discussion of research on the afore-mentioned properties of aloe vera.

An Indian study in 2011 used compounds to induce inflammation and paw edema in albino Wistar rats. In addition various standard methods were used to indicate sensitivity to pain.  Aqueous extracts of whole leaf of aloe vera was administered in various concentration to the Wistar rats. Carrageenan and formaldehyde was injected into the paws to induce inflammation and edema. In addition, tail flick, hot plate and acetic acid were used to induce pain and measure the analgesic effects of the aloe vera extracts. These are standard methods to induce pain in rats and measure analgesic effects. The researchers found a significant dose-dependent reduction in paw edema with aloe vera extract. In addition, there was a significant reduction in pain from acetic acid and from a thermal stimulus in a dose-dependent fashion from aloe vera extract. The latter reduction was comparable to the reduction from indomethacin. No toxicity was noted at 600 mg/kg (33).

Another study in 2014 in India examined the use of an ethanolic extract of aloe vera in pain reduction after a sciatic nerve ligation in adult female Wistar albino rats. In the introductory section the paper notes that Aloe vera has been shown to act on nuclear factor Kappa beta (NF k beta), Her2/Neu, caspase and matrix metalloproteinases. NF k beta is a DNA transcription factor that causes transcription of certain genes in response to various physical stressors as well as microbes in the body. In particular, NF kbeta can cause transcription that results in inflammation.  Her2/Neu is a receptor on the cell membrane when activated results in transcription of an oncogene. It is particularly involved in breast cancer. Caspases are a family of protease enzymes that play an essential role in programmed cell death. Matrix metalloproteinase is a protease involved in a number of cellular processes including cell proliferation, migration, differentiation, angiogenesis, apoptosis and host defense.  It is also known that A. vera inhibits cyclooxygenase thereby reducing prostaglandin E2 production from arachidonic acid. In this placebo-controlled study, the sciatic nerve was ligated in the experimental group of adult female Wistar rats. Two different doses of the ethanol extract of aloe was administered by mouth to the experimental group and a third group received gabapentin by mouth. Thresholds for cold-water immersion, thermal hyperalgesia, cold and mechanical allodynia were tested weekly out to 21 days following sciatic nerve ligation. An increased threshold for nociception was noted with thermal hyperalgesia, chemical hyperalgesia and mechanical allodynia. In addition, a significant improvement in antioxidant parameters including superoxide dismutase, catalase, glutathione and lipid peroxidation was noted. The authors conclude, “The results of the present study validate the use of EEAV (ethanolic extract of A. vera) to treat neuropathic pain. This effect may be attributed to the decreased migration of neutrophils and due to the antioxidant properties of A.vera”(34).

A Nigerian study in 2011 reported on the analgesic and anti-inflammatory effects of aqueous extracts of Aloe vera (Aloe barbadensis) in Wistar rats. Formalin was injected into the hind paw to measure the anti-inflammatory effect of A. vera and acetic acid was injected into the peritoneal cavity to measure the analgesic effect. The authors report that the hind paw edema was reduced at 3 hours after intraperitoneal injection of A. vera. In the analgesic study, three different doses of aloe vera injected intraperitoneally all resulted in a significant drop in the “writhing” reaction of the rats to the acetic acid. The authors conclude, “The present study showed that the aqueous extract of Aloe barbadensis has anti-inflammatory and analgesic activities that could be mediated via modulators of pain and information or through central activity” (35).

An African study in 2011 examined the analgesic efficacy as well as potential adverse effects of A. vera in Wistar rats. “Both visceral and somatic pain in animals was assayed using radiant heat method, hot plate method and writhing test.” To test for sub-acute toxicity, A vera was administered by mouth at 300 mg/kg for 14 days. Biochemical analysis of blood and histopathological study of GI mucosa was performed after 14 days. The authors report that the aqueous extract of A. vera resulted in significant analgesia in the radiant heat and hot plate method of pain induction. The writhing method showed a 51.17% inhibition of pain. There were no microscopic abnormalities of the GI mucosa and no abnormalities of renal or hepatic function (36).

Sesame seed oil
Sesame oil is quite ancient with its use recommended in the Vedas. The Vedas are ancient texts from India dating to the second millennium BC. It was recommend in the Vedas to promote general health. Ayurveda, the indigenous medical system of India regards sesame oil as the queen of oils due to its benefit for so many health issues. In terms of its history, charred remains of sesame have been recovered from archeological excavations dating to 3500-3050 BC.  Sesame was used by the Babylonians and the Persians. The plant, Sesame, tends to grow in tropical regions, particularly Africa and India. It will grow in drought like conditions when other plants fail to grow. Sesame seed has one of the highest content of oil of any seed. Sesame seed oil is composed of linoleic acid (41% of total), oleic acid (39%), palmitic acid (8%), stearic acid (5%) and others in small amounts. In addition, the oil contains tocopherols with a predominance of gamma-tocopherol (90.5%). The phytosterol marker β-sitosterol accounted for 59.9% of total sterols contained in sesame seed oil. Phytosterols are plant-derived sterols, a class of compounds that are a subgroup of steroids. The molecules consist of 4 linked 6-carbon rings with various attached side groups. The hull of the seed contains the lignans sesamin and sesamolin. Lignans are one of the four classes of phytoestrogens, compounds structurally similar to estradiol. There is some evidence that the lignans in sesame interact with vitamin E and may, in part, be responsible for the anti-aging effect of sesame. In addition, the oil contains vitamin E and K, the minerals magnesium, copper, calcium, iron and zinc and vitamin B6. The gel has been used for numerous conditions. Topically is has been studied for burn wounds, genital herpes, and seborrheic dermatitis. Other studies have reported on the use of aloe vera for Psoriasis vulgaris, skin moisturizer, Type 2 diabetes, oral lichen planus infections, angina pectoris, ulcerative colitis, kidney stones and alveolar osteitis.

The first study on the use of topical sesame seed oil is a 2015 paper on a study in Iran on patients with upper or lower extremity trauma.  This was a controlled study in which the experimental group received topical sesame oil on the painful traumatized areas and the control group received routine care. Pain levels and use of NSAIDS was measured multiple times during the hospital stay. A significant benefit in pain control was noted in the experimental group with significantly less use of NSAIDS. The authors conclude, “Topical application of sesame oil could reduce pain severity and frequency of received NSAIDS in patients with upper and lower extremity trauma. Therefore, it is recommended to use this oil in complementary medicine for pain relief due to low cost, easy usage and lack of adverse effects” (37).

A Brazilian study in 2014 reports on a study to examine the antinociceptive and anti-inflammatory activity of sesame oil and sesamin in Wistar rats. In the introduction, the authors point out that the lignans sesamin, and sesamolin as well as gamma tocopherol offers a high oxidative stability to sesame oil. They also note that sesamin and sesamolin have shown high anti-oxidant, antiproliferative, antihypertensive and neuroprotective activities. In addition, they lower cholesterol levels and increase hepatic fatty acid oxidation enzymes.  In the study, analgesia was tested using rate injected with acetic acid into the peritoneal cavity and measuring the degree of “writhing”. They also measured nociception by injecting formalin into the paws of the rats and measured the duration of licking of the paws. They also placed rats on hot plates and measured latency time, presumably before movement. They also immersed their tail in hot water, injected carrageenan into their paws to measure anti-inflammatory activity as well as injecting formalin into the pleura. (I don’t suppose anti-animal abuse groups made decisions in regards to ethical standards for this type of experimentation).  The investigators found that sesame oil and sesamin reduced writhing, increased reaction time on a hot plate, and produced a significant result in tail immersion. Both sesame oil and sesamin reduced paw edema. Both the exudate volume and leucocyte migration were reduced. The authors conclude, “These results suggest that sesamin is one of the active compounds found in sesame oil and justify the antinociceptive and anti-inflammatory properties of this product”(38).

An interesting study in Taiwan was reported in a 2016 article. The study measured the effect of sesame oil after experimental sciatic crush injury in mice. This was a controlled study with multiple experimental group taking different amounts of oral sesame oil. They also performed somatosensory evoked potentials. They report that the experimental group revealed significantly reduced lipid peroxidation as a well as increased GAP43 and nuclear Nrf2 in the crushed sciatic nerve. GAF43 is a neuronal growth factor found in the growth cones of neurons.  Nuclear Nrf2 is a transcription factor for genes responsible for anti-inflammatory proteins. In addition, they found improved electrophysiological and functional properties in the crushed sciatic nerves of mice receiving sesame seed oil. They conclude by saying “Further, application of natural product sesame oil may be an alternative approach for improving functional recovery in the clinical setting” (39).

There are at three articles demonstrating the protection of sesame oil, both in vitro and in vivo, in the presence of different insult to the central nervous system. These results may have significance for the peripheral nervous system. A Taiwanese study in 2011 studied the role of sesamin in status epilepticus in rodents induced by kainic acid. The mortality decreased from 22% to 0 percent. Other observations include a significant (around 50%) increase alpha tocopherol and significant decrease in malondialdehyde. Malondialdehyde is a metabolic product of polyunsaturated fatty acids exposed to reactive oxygen species, a marker for stress. Sesamin also preserved superoxide dismutase (the enzyme that neutralizes the superoxide radical, a powerful reactive oxygen species), which fell in control animals not given sesamin.  A number of measurements were conducted on PC12 cells exposed to Kainic acid with an experimental cell line protected by sesamin oil.  PC12 is a cell line derived from a pheochromocytoma of the rat adrenal medulla. In particular, the sesamin exposed PC12 cells had decreased release of calcium ions, reactive oxygen species, and malondialdehyde.  The latter three are “markers” for increased oxidative stress. Using western blot analysis, a sensitive analysis of proteins, sesamin appears to significantly decrease ERK1/2 involved in a cascade of events to alter gene transcription in the face of a threat a threat to the organism. There was also significant reduction of caspase-3, a member of a family of proteases involved in apoptosis, programmed cell death. There was also a significant reduction of COX-2, an enzyme involved in the conversion of arachidonic acid to prostaglandin H2 an important precursor of prostacyclin. Prostacyclin is a member of the class of prostacyclins, which are involved in inflammation. The authors conclude “Taken together, it suggests that sesamin could protect KA-induced brain injury through anti-inflammatory and partially anti-oxidative mechanisms (40).

An additional Taiwanese study in 2006 examined the benefit of sesamin or crude sesame oil (containing sesamolin) on infarct size in gerbils. The right carotid artery and right middle cerebral artery were occluded and infarct size was measured using a special stain. The infarct size was reduced by approximately 50% suggesting that sesamin and sesamolin “exert effective neuroprotection against cerebral ischemia” (41).

Bacopa
Bacopa monnieri, also called water hyssop, brahmi, herb of grace, Indian pennywort, is an annual creeping plant found in the wetlands of southern and eastern India as well as Australia, Europe, Africa, Asia and the Americas. The name Brahmi derives from Brahma, the first of the Hindu trinity of Gods. The aerial parts of the plant are used medicinally. Bacopa is part of the ancient Ayurvedic medical system of India used for mental disorders and loss of intellect and memory. Numerous studies show benefit for learning, memory and pain.  An interesting study related to its benefit for pain was a 2011 study from Pakistan showing that the administration of an extract of Bacopa prevented tolerance to morphine analgesia in mice (42). Ethanolic extracts of the plant reveal alkaloids, sterols, saponins, d-mannitol, acid A and betulinic acid. Neuropharmacologic effects appear to be due mainly to saponins called bacoside A and B.

Multiple studies suggest a significant benefit of Bacopa for neuropathic pain. Two studies are of particular interest. The first study from Pakistan studied the benefit of Bacopa in reducing allodynia and hyperalgesia in the chronic sciatic nerve constriction injury model in rats. Loose ligatures were placed around the sciatic nerves of 8 groups of rats. One group received oral Bacopa and another gabapentin. There was a control group as well as a sham-operated group. Different dosages of Bacopa were used. They conclude with “In summary, this study demonstrates for the first time that a bacoside rich fraction of Bacopa monnieri presents marked antinociceptive properties by alleviating allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats. Bacopa monnieri may constitute a beneficial herbal remedy for the efficient management of neuropathic pain syndromes” (43).

A second study demonstrated the neuroprotective effect of Bacopa in a rat model of diabetic neuropathic pain. Healthy Sprague Dawley rats were administered streptozotocin intraperitoneally to cause the rats to develop diabetes mellitus. Animals with blood glucose over 250 mg/dl were used in the study. Cold and hot immersion of the tail of the rats and formalin injection into the left hind paw were used to demonstrate the presence of diabetic neuropathy. The experimental group of rats, injected with an extract of Bacopa, injected intraperitoneally, revealed a significant reversal of the hyperalgesia in diabetic rats. Injection of an adenosine A1-receptor antagonist completely reversed the benefit of Bacopa, revealing that the analgesic effect of Bacopa was related to its action at the adenosine A1 receptor. The authors discuss the role of adenosine receptors for spinal antinociception. Since the adenosine receptor is linked to a number of effectors, the exact mechanism of adenosine A1 agonism in reducing pain is not known at this time (44).

Shankhpushpi
Shankhpushpi can refer to any of four different species of ayurvedic herbs. For our purposes, we are referring to convolvulus pluricaulis (C pluricaulis). Shankhpushpi is considered Medhya Rasayana, meaning it belongs to a class of herbs that can improve memory and intellect. Medha means intellect and Rasatan means “therapeutic procedure or preparation that on a regular practice will boost nourishment, health, memory, intellect, immunity and hence longevity.” (45) Phytochemical studies of Convolvulus pluricaulis reveal carbohydrates, proteins and amino acids, alkaloids including shankhapushpi, fatty acids and phenolics, Glycosides, triterpenoids and steroids. Tropane alkaloids are considered to be important constituents. (46)

Much of the literature is from the east and quite informative. A number of the studies relate to the clinical benefits and pharmacologic mechanisms of constituents in the herb. For example, a study from the University of Rhode Island and two medical centers in New Delhi. was a relatively sophisticated study examining the effect of Convolvulus pluricaulis on rats given scopolamine. The authors note that C.

pluricaulis can improve antioxidant levels by improving glutathione peroxidase and reduced glutathione. C. pluricaulis also reduces levels of acetylcholine esterase, thereby increasing levels of acetylcholine and lowers lipid peroxidation. This study used aqueous extracts of C. pluricaulis in Wistar rats who received scopolamine. It was known, previous to this investigation that C. pluricaulis reduced memory impairment in rats given scopolamine and that scopolamine increased messenger RNA biomarkers of Alzheimer disease, beta amyloid precursor protein (AbetaPP) and tau. The researchers found that C. pluricaulis reduced the scopolamine induced increase in messenger RNA for AbetaPP and tau (47).

Another study from Saudi Arabia and India confirmed the presence of flavonoids, alkaloids, triterpenoids and saponins in C. pluricaulis. They go on to describe the presence of the alkaloid shankhpushpi, the tropane alkaloids convolamine and scopoletin, cetyl alcohol, the flavonoid kaempferol and the steroids phytosterol and beta-sitosterol. They demonstrated that three different extracts had anti-convulsant and anxiolytic activity. This activity of the extracts is compatible with the agonist activity of the constituents noted above at the GABA-A receptor (48)

In regards to the cholinergic activity producing analgesia, two studies are of interest. A 1998 study at Abbott Labs used a synthetic nicotinic acetylcholine receptor agonist called ABT-594. This compound had no opioid receptor activity. It was found that subcutaneous administration of ABT-594 in anaesthetized rats reduced pain transmission but did not interfere with transmission non-noxious and mechanical stimuli. The effect was equal to morphine but ABT-594 did not appear to elicit opioid-like withdrawal nor physical dependence (49)

An interesting 2007 study from Japan studied the role of acetylcholine in the deep dorsal horn neurons of the adult rat spinal cord. In the presence of glutamate blockers, the researchers demonstrated that nicotine significantly increased inhibitory postsynaptic potentials of lamina V neurons in the deep dorsal horn of the spinal cord. They conclude with “These results suggest that several nAChR subtypes are expressed on the presynaptic terminals, pre terminals, and neuronal cell bodies within lamina V and that these nAChRs are involved in the modulation of inhibitory synaptic activity in the deep dorsal horn of the spinal cord” (50).

In regards to shankhpushpi, the cholinergic activity noted in paragraph two above, and the GABAergic activity noted in paragraph 3, both suggest pain inhibitory activity of this herb. Given the wide variety of constituents, as well as the known nootropic effect, shankhpushpi should diminish pain and promote healing when applied topically to areas of neuropathic pain.

St. Johns Wort oil
St. John’s Wort dates back to classical antiquity (Greco Roman empire) and apparently was a component in a Theriac, or panacea (rom Panacea, the Goddess of universal remedy). The history of Theriacs, dating over 200 years is of interest, and initially conceived as a universal antidote to an external toxic agent. The power of Theriacs apparently led to the conception of a panacea.  For the reader interested in the clinical history Of St. John’s Wort, I would recommend the on-line article by Christopher Hobbs PhD St. John’s Wort: Ancient Herbal Protector. In addition to its ancient use for wounds, and the bites of any venomous creature, it was also used for kidney disorders, and as a febrifuge, vermifuge, as well as for gout and rheumatism. It was also known for repelling undesirable influences and promoting good luck. It is best known for its use in “Nervous disorders”, particularly depression (51)

The reader should note that although there are some recent studies in peer reviewed journals, the bulk of information on the clinical use of St. John’s Wort comes from its traditional usage in herbal medicine. For example, in an online article by Angela Justis (52), the author quotes the herbalist Mary Bove, who states “St. John’s Wort is known for helping to diminish pain”. Justis goes on to state St. John’s Wort can diminish pain “both externally and internally”. She goes on to note “Specifically indicated for trauma and damage to the nervous system whether through injury or viral infection, St. John’s Wort is the herbalist go-to for painful issues such as neuralgias, sciatica, Bell’s palsy, head and spine trauma, pinched nerves, after surgical and dental work, as well as injuries to any area that is rich in nerve endings”.

In a 2013 article from the Department of Dermatology, University Medical Center Freiburg, the authors describe in detail, the topical attributes of St. John’s Wort. In regards to anti-oxidative effects, they note that St. John’s Wort reduces superoxide levels in a cell free model and human vascular tissues. They also note that SJW demonstrated antioxidant activity in a dose-dependent manner against DPPH. DPPH is a chemical compound composed of free radicals and used to determine antioxidant properties of various molecules. They also note that the antioxidant property of SJW is not surprising given the 10% content of flavonoids, well known antioxidants (53).

The same authors just quoted above also have an extensive section of the anti-inflammatory property of topical SJW. In particular they discuss the anti-inflammatory effects of hyperforin, a constituent in SJW. Hyperforin inhibits COX1 and lipoxygenase as well as down regulation of a cascade of inflammatory molecules including IFN-gamma, and matrix metalloproteinase 9. Hypericin, another constituent of SJW did not seem to possess the anti-inflammatory effects of hyperforin. It should be added that the authors also discuss other properties of SJW including anticancer effects and wound healing as well as its benefit in atopic dermatitis, herpes simplex and psoriasis. There is also a discussion of its potential for photosensitization. They do note “It has however been shown that therapeutic oral doses of SJW extracts taken for treatment of mild to moderate depression do not cause photosensitization to a clinically significant degree”.

Although somewhat limited, there are a number of articles reporting on the analgesic effects of SJW.  There is an extensive review from the University of Florence in 2017. They note “Preclinical animal studies demonstrated the ability of low doses of SJW dry extracts (0.3% hypericins; 3-5% hyperforin) to induce antinociception, to relieve from acute and chronic hyperalgesic states and to augment opioid analgesia.” (54) They go on to state, “In vivo and in vitro studies showed that the main components responsible for the pain relieving activity are hyperforin and hypericin. SJW analgesia appears at low doses (5-100 mg/kg), minimizing the risk of herbal-drug interactions produced by hyperforin, a potent inducer of CYP enzymes”.

An interesting paper from the University of Florence in 2010 reported on the analgesic effect of SJW in two rat models of pain; the first was a chronic nerve constriction injury and the second involved administration of oxaliplatin. SJW reversed hyperalgesia. Studies of the periaqueductal gray matter in controlled rats revealed robust over-expression and hyperphosphorylation of the molecules PKC gamma and PKCepsilon. These molecules are known as a substrate for hyperalgesia. SJW in the experimental rats revealed significant reduction of phosphorylation of these molecules. This appeared to be due to the hypericin in the SJW. Of interest is that hyperforin antinociception involves an opioid-dependent pathway suggesting a dual mechanism of analgesia of SJW (55).

Several studies have shown a significant benefit of SJW in rat models of diabetic pain.  A Turkish study in 2010 treated rats with streptozotocin. The rats developed diabetes with neuropathy. Administration of SJW decreased high blood glucose levels. As well as a reduction in mechanical hyperalgesia. (56)  A second Italian study in 2014  also used the streptozotocin model of rat diabetes with neuropathy. SJW reduced the hyperalgesia and the authors go on to state “The antihyperalgesic efficacy of these herbal drugs was comparable to that of clinically used antihyperalgesic drugs (carbamazepine, lamotrigine, l-acetyl carnitine)” (57).

Alpha Lipoic Acid
Alpha lipoic acid (ALA), or lipoic acid is an organic molecule manufactured in multiple vegetables as well as animals, including humans.  It is a unique, strong antioxidant due to its structure with an acidic water-soluble carboxyl group at one end and a lipid soluble 4-carbon chain ending in a pentagonal ring with two sulfur atoms bonded together (disulfide bond). The molecule can exist in two mirror image states S and R, with the R form being biologically active. The reduced form of lipoic acid occurs when the bond between the two sulfur atoms is broken (dihydrolipoic acid). The difference in energy states between lipoic acid and dihydrolipoic acid is large allowing it to reduce many types of free radicals such as the hydroxyl radical, singlet oxygen and peroxynitrite. ALA also reduces vitamin C, vitamin E and glutathione when they become oxidized. Given this broad anti-oxidant capacity and the fact that it is both water and fat-soluble accounts for its status as an “ideal antioxidant”.  ALA is considered a pleiotropic compound because of its multiple functions in human metabolism (58).  It is a cofactor in at least 5 enzyme systems including at 2 sites in the citric acid cycle, a major metabolic system that yields energy from nutrients. This underlies the importance of ALA for mitochondrial function.  In addition, lipoic acid plays a role in signal transduction pathways. A signal transduction pathway is a cascade of metabolic steps initiated by a chemical signal resulting in a defined cellular activity. In particular, ALA acts at many points in the insulin pathway. This may explain its clinical benefit in diabetes mellitus.

Lipoic acid reduces oxidative stress, a condition where free radicals exceed reducing capacity. Oxidative stress played a significant role in the pathophysiology of peripheral neuropathy in a chronic constriction injury in a rat model (59).  A 2004 paper from the Department of Neurology, University of Michigan, discusses the role of oxidative stress in the pathogenesis of diabetic neuropathy.  The authors state “Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism. Diabetes overloads glucose metabolic pathways resulting in excess of free radical production and oxidative stress” (60). An additional 2014 paper discusses the role of oxidative stress along with mitochondrial dysfunction in chemotherapy induced peripheral neuropathy (61)

Oral treatment with alpha lipoic acid for diabetic neuropathy has ben well studied. A 2012 meta-analysis of four trials from the Netherlands in which ALA was administered 600mg IV daily in the experimental group for three weeks. There was a significant improvement in pain, burning and numbness in the experimental group. The authors conclude “The results of this meta-analysis (600mg.day I.V.) over 3 weeks is safe and significantly improves both positive neuropathic symptoms and neuropathic deficits to a clinically significant degree in diabetic patients with symptomatic polyneuropathy (62).

There are multiple reports on the anti-inflammatory effects of lipoic acid. An experimental study from China in 2015 studied the anti-inflammatory effects of alpha lipoic acid on mesangial cells exposed to lipopolysaccharide. They noted that ALA reduced the levels of inflammatory cytokines such as TNF alpha, interleukin beta and interleukin 6 released from the mesangial cells. ALA also reduced levels of COX-2 and inducible nitric oxide. The authors also note that ALA inhibited the inflammatory NF kappa beta pathway (63).

A Turkish study studied the anti-inflammatory effect of ALA on rats who received an injection of the inflammatory substance carrageenan into a hind paw. They measured the levels of multiple endogenous antioxidants as well as markers of inflammation. They conclude, “…these results suggest that the anti-inflammatory properties of ALA, which has a strong antioxidant potency, could be related to its positive effects on the antioxidant system in a variety of tissues of the rats” (64).

Two most causes of neuropathy, diabetes and alcoholism, appear to have an inflammatory component.  A 2013 German study, measured the correlation of pro and anti-inflammatory markers with diabetic neuropathy in 1047 participants. They conclude that “diabetic distal sensorimotor polyneuropathy is linked to proinflammatory and anti-inflammatory, possibly compensatory, processes in the older general population”.(65).

A 2013 study from King’s College London examined the role of “neuroinflammation” in the generation of neuropathic pain. The authors state “Diverse causes of neuropathic pain are associated with excessive inflammation in both the peripheral and central nervous system which may contribute to the initiation and maintenance of persistent pain. Chemical mediators, such as cytokines, chemokines, and lipid mediators, released during an inflammatory response have the undesired effect of sensitizing and stimulating nociceptors, their central synaptic targets or both.” (66)

The inclusion of ALA in Nerve Balm is based upon all the considerations above.

 Lion’s Mane
Lion’s mane (Hericium erinaceus) is a unique fungus, resembling a beautiful waterfall. It is purported to taste like seafood and has over 1000 years of use in Chinese medicine. It is native to North America, Asia and Europe. It is generally found late summer into autumn and grows on dead and dying hardwoods in the wild. The fruiting body is the part of the mushroom above ground and is the part of the mushroom traditionally foraged and consumed. It contains polysaccharides including beta-glucans, heteroglucans and heteroxylans which support immune health, normal healthy cell growth and turnover. In general, the fruiting bodies and mycelia (the underground part of the mushroom) contain compounds that have been shown to be antibiotic, anticarcinogenic, antidiabetic, antifatigue, antihypertensive, antihyperlipidemic, antisenescence, cardioprotective, hepatoprotective, nephroprotective as well as neuroprotective decreasing anxiety, depression and improving cognition (67). Lion’s mane has ingredients that cross the blood brain barrier and considered neurotrophic (supporting the growth, differentiation, and survival of nerve cells). In fact, Hericium eranceus is well proven to increase the body’s production of nerve growth factor (NGF), the first human neurotrophic factor to be described. Multiple constituents of Hericium erinaceus are of low molecular weight, cross the blood brain barrier and support myelin production as well as influencing the production of NGF. The fruiting body also contains cyathane diterpenoids known as hericenones and erinacines.The cythane backbone is a tricyclic structure, each carbon cycle containing between 5 and 7 carbons. . Numerous side groups form the different diterpinoids. Most of the hericenones and erinacines promote NGF biosynthesis in rodent cultured astrocytes (68). In particular, of the 8 hericenones, 4 promoted NGF synthesis. Numerous eranicines are isolated from the mycelium. There structures are similar to the hericenones and they are more potent stimulators of NGF synthesis than the hericenones. There are several signaling pathways involved in the stimulation of NGF synthesis. These involve kinase proteins that add phosphate groups to molecules (from ATP) which changes the three-dimensional structure of the molecule. Readers interested in more detail may refer to the article by K.H.Wong et al (69). The authors in the aforementioned article studied the efficacy of an aqueous extract of H. erinaceus on a crush injury to the peroneal nerve in rats. They observed that return of function in muscles controlled by the peroneal nerve occurred earlier in the experimental group than the control group. They also used a hot plate test to measure the speed of recovery of sensory axons in the peroneal nerve. The treated group recovered at a significantly faster rate than the control group. Of interest was the detection of activation of the kinase signaling pathway in the dorsal root ganglia in the experimental group. The dorsal root ganglia is a collection of sensory nerve cell bodies adjacent to the spine, the axons of which extend down the hind limb as far as the foot. They go on to discuss that the Akt signaling pathway inhibits programmed cell death and the MAPK pathway is essential for neurite outgrowth, regeneration, synaptic plasticity and memory functions in mature neurons. 

   Another interesting study was the effect of Lions Mane on recovery from cisplatin induced neuropathy in mice. They conclude “HE (Hericium erinacius) exhibited therapeutic effects on a mouse model of peripheral neuropathy…” This included faster return of normal EMG findings as well as immunohistochemical signs of significant myelin and axon regeneration in treated animals (70). 

   An additional experimental study from Malasia involved recovery from an induced peroneal injury in Sprague-Dawley rats. They compared a control group against a group treated with an aqueous extract of Hericium erinaceus. They conclude “These resu;lts suggest that daily administration of aqueous extract of H. erinaceus fresh fruitbodies has a beneficial effect on the recovery of injured rat peroneal nerve in early stages of regeneration (71).

Clove essential oil  
Cloves are the unopened flower buds of the clove tree native to old world tropics, particularly the Moluccas (Spice Islands) in Indonesia.  It is an evergreen tree about 40 feet tall. Clove were known in China at least 2000 years ago and in Europe by the fourth century A.D. Curiously, the Dutch, in an attempt to control the clove trade, cut down all the clove trees in the Moluccas except for one island. They held the monopoly for 150 years. Ultimately the French smuggled seeding clove trees to Mauritius, an island on the east side of Africa and by 1800 clove trees were cultivated in other islands in the Indian ocean. Currently islands belonging to Tanzania produce 90% of the world’s cloves. 

Clove oil was used for a number of indications in Chinese Medicine. The oil is analgesic, anti-bacterial, antifungal, insecticidal, anti-inflammatory and anti-oxidant. It is also anti-vomiting and anti-spasmodic. It is used in aromatherapy and used orally for asthma and various allergic disorders/ In western countries, clove oil has found a place in dentistry as an analgesic and “disinfectant”. The main component of clove oil is eugenol, a simple “allylbenzene” molecule comprising 80-90% of the chemical constituents of clove oil. The oil also contains over 38 compounds including the sesquiterpene beta-caryophyllene as well as other sesquiterpenes. It also contains vanillin, crategolic acid, several tannins, methyl salicylate and triterpinoids. Most of the research on clove oil focusses on eugenol.

Worldwide, eugenol is used as a dental analgesic. It definitely allays tooth pain. Multiple mechanisms are involved in its analgesic mechanism. It inhibits voltage-gated sodium channels similar to local anesthetics. The influx of sodium through sodium channels is essential to conduction of the nerve impulse (action potential) and nerve conduction cannot occur if the sodium channel is blocked. Another mechanism is the effect of eugenol on GABA receptors. A 2017 paper reported on a study showing that aqueous extracts of clove “significantly and specifically potentiated the GABA-induced currents…) (72). HPLC-based fractionation revealed eugenol as the primary compound for the Gaba-ergic activity. Acetyleugenol, a minor component of the extract revealed even higher gaba-ergic activity. GABA is the main inhibitory neurotransmitter in the nervous system and, in particular, an inhibitor of pain transmission. Two Korean studies found that eugenol inhibits calcium influx via the high-voltage-activated calcium channel (73) as well as voltage-gated potassium currents (74). Inhibition of potassium influx inhibits production of the travelling nerve potential (action potential). Increased intracellular calcium promotes pain transmission in peripheral nerves. 

There are multiple experimental studies on the benefits of eugenol or clove extracts for neuropathy or its analgesic effect. A Scottish study reported on in 2006 examined the effect of eugenol on streptozocin-induced diabetic rats. Eugenol was given orally after six weeks of untreated diabetes mellitus. Conduction velocity studies showed values that did not appear affected by the diabetes. Sciatic nerve endoneurial blood flow was corrected by Eugenol. Other measured parameters showed improvement with the Eugenol. The authors conclude “Thus, aspects of both vascular and neuronal complications in experimental diabetes are improved by eugenol, which could have therapeutic implications for diabetic neuropathy and vasculopathy” (75).

 An Iranian study reported in 2013 studied the analgesic effect of aqueous and ethanolic extracts of clove in ninety male mice divided into nine groups. These included a placebo group, those treated with aqueous extracts of clove, others with ethanolic extracts of clove and those receiving naloxone along with the extracts. The mice were exposed to a hot plate inducing nociception. The authors conclude “The results of the present study showed that aqueous extract of clove has analgesic effects in mice demonstrated by hot plate test which is reversible by naloxone. The role of the opioid system in the analgesic effect of clove might be suggested…” (76)

Another interesting Korean study reported in 2011 focussed on hyperpolarization-activated cyclic nucleotide-gated channels and their current, I(h). They mention that these channels may play an important role in neuropathic pain. The complete article is not available, only the abstract. It appears the experiment was on an experimental animal, probably rats. They performed a chronic constriction injury on the infraorbital nerve which caused mechanical allodynia in the orofacial area. The allodynia was reversed by eugenol and the experimenters were also able to determine that eugenol inhibited the I(h) current in injured trigeminal ganglion cells. The required dose of eugenol was lower than the dose required to inhibit voltage-gated sodium channels. They conclude “ We propose that eugenol could be potentially useful for reversing mechanical allodynia in neuropathic pain patients (76).

The last study we will mention is a Canadian study reported in 2010. A sciatic nerve ligation was performed in male Sprague-Dawley rats. Eugenol was injected intrathecally at the lumbar level. Mechanical allodynia was significantly reduced with intrathecal eugenol which was noted to have penetrated the CNS well. They conclude “The results support the hypothesis that eugenol may alleviate neuropathic pain, both allodynia and hyperalgesia, by acting centrally most probably at the level of the dorsal horn of the spinal cord where vanilloid receptors can be found” (78).

GABA
There are variable estimates of the percent of glutamate and GABA synapses in the nervous system. Some estimates of glutamate synapses are as high as 90% and GABA synapses as high as 30%. Glutamate is the main excitatory neurotransmitter in the nervous system and GABA the main inhibitory neurotransmitter. The resting potential across the neural membrane is -65 to -70mV. Inhibitory neurotransmitters increase this negative potential thereby preventing formation of the nerve impulse (action potential). Excitatory neurotransmitters decrease this potential allowing, at a certain point, formation of the action potential which travels along the axon, eith towards or away from the nerve cell body. GABA is synthesized from glutamate via an enzyme glutamate decarboxylate (GAD) using B6 (pyridoxal phosphate) as a co-factor. 

There are two GABA receptors, the simpler A one in which GABA opens a channel or pore in the neural membrane allowing chloride influx or potassium efflux, thereby raising the transmembrane potential. The GABA-B receptor is called metabotropic which uses an intermediary, the G protein, to open or close the ion channel.

The role of GABA at the endings of pain fibers has not been elucidated completely. A 2006 report from a degree project at a university in Uppsala, Sweden found that baclofen (a GABA agonist) inhibited the ability of Schwann cells, the insulating cells of axons, to proliferate (79) There are GABA receptors on Schwann cells and GABAA is found within thin caliber axons and neural cell bodies. Slowly conducting pain C fibers are thin caliber axons. If the Schwann cells do not proliferate then the pain fiber axons will conduct slowly or not at all. 

Another well described role of GABA is in the function of Pacinian corpuscles in the skin. Pacinian, or lamellar corpusles are one the four types of mechanoreceptors in hairless mammalian skin. They respond to vibration and pressure. Studies have shown that the lamellar cells release GABA inhibiting the GABA receptor on the nerve ending (80). 

 An Italian study published in 2014 involved a partial sciatic nerve ligation in Sprague Dawley rats. Two molecules that act on GABA receptors were administered at the time of the ligation. These molecules or ligands were baclofen and CGP56433. Tactile hypersensitivity was reduced and changes in the structure and myelin was also observed. The authors conclude “Peripheral synergistic effects, via GABA-B receptor activation, promote nerve regeneration and likely ameliorate neuropathic pain (81).

FOOTNOTES

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11.   Ripps H and Shen W Review: Taurine: a “very essential” amino acid. Mol Vis. 2012;18:2673-86

12.  Schmidt C E Role of Taurine in the central nervous system. J Biomed Sc. 2010 Aug 24;17 Suppl 1:S1

13.  Wu H et al Mode of action of taurine as a neuroprotector. Brain Res. 2005 Mar 21;1038(2):123-31;172(1):211-9

14.  Obrosova IG et al Taurine counteracts oxidative stress and nerve growth factor deficit in early experimental diabetic neuropathy. Exp Neurol. 2001 Nov;172(1):211-9

15.  Terada T et al Antinociceptive effect of intrathecal administration of taurine in rat models of neuropathic pain. Can J Anaesth. 2011 Jul;58(7):630-7

16.  Devor M Sodium channels and mechanisms of neuropathic pain. J Pain. 2006 Jan;7( 1 Suppl 1): S3-S12

17.  Molnar Pand Erdo SL Vinpocetine is a potent as phenytoin to block voltage-gated sodium channels in rat cortical neurons. Eur J Pharmacol. 1995 Feb 6;273(3):303-6

18.  Zhou X et al Vinpocetine is a potent blocker of rat NaV1.8 tetrodotoxin-resistant sodium channels. J Pharmacol Exp Ther. 2003 Aug;306(2):498-504

19.  Stewart David The blood-brain barrier. http://www.oilhealer.com/bloodbrain.cfm

20.   Wikepedia article on isoprene

21.  Stewart David   The blood-brain barrier http://www.oilhealer.com/nloodbrain.cfm

22.  De Souza DP Analgesic-like activity of essential oil constituents. Molecules. 2011 Mar 7;16(3):2233-52

23.  Santos FA and Rao VS Antiinflammatory and antinociceptive effects of 1,8-cineole, a terpenoid oxide present in many plant essential oils.  Phytother Re. 2000 Jun;14(4):240-4

24.  Galeotti N et al Menthol: a natural analgesic compound. Neurosci Lett. 2002 Apr 12;322(3):145-8

25.  Hall AC et al Modulation of human GABA and glycine receptor currents by menthol and related monoterpenoids. European J of Pharmacology. Volume 506, issue 1. Dec 3, 2004 pp 9-16

26.  Davies SJ et al A novel treatment of postherpetic neuralgia using peppermint oil. Clin J Pain. 2002 May-June; 18(3):200-2

27.  Jiang Y et al chemical composition and anti-microbial activity of the essential oil of rosemary. Environmental Toxicology and Pharmacology. Vol 32, Issue 1, July 2011, pp 63-68

28.  Same as #26 above

29.  Him Aydin et al Antinociceptive activity of alpha-pinene and fenchone. Pharmacologyonline 3:363-369 (2008)

30.  Peana AT et al Effects of (-)-linalool in the acute hyperalgesia induced by carrageenan, L-glutamate and prostaglandin E2. Eur J Pharmacol. 2004 Aug 30;497(3):279-84

31.  Batista PA et al The antinociceptive effect of (-)-linalool in models of chronic inflammatory and neuropathic hypersensitivity in mice. J Pain. 2010 Nov;11(11):1222-9

32.  Devaraj E and Karpagam T Evaluation of anti-inflammatory activity and analgesic effect of Aloe Vera leaf extract in rats. Internation Research Journal of Phamacy. On-line at http://www.irponline.com

33.  Ibid

34.  Kanyadhara S et al Ethanolic extract of Aloe vera ameliorates sciatic nerve ligation induced neuropathic pain. Anc Sci Life. 2014 Apr-Jun; 33(4): 208-215

35.  Egesie U.G. et al Anti-inflammatory and analgesic effects of aqueous extract of Aloe vera (Aloe barbadensis) in rats. Afr. J. Biomed. Res. 14 (September 2011):209-212

36.  Ghosh AK et al A study on analgesic efficacy and adverse effects of Aloe vera in Wistar rats. Pharmacologyonline 1:1098-1108 (2011)

37.  Shamloo B et al The effects of topical sesame (sesamum indicum) oil on pain severity and amount of received non-steroid anti-inflammatory drugs in patients with upper and lower extremities trauma. Anaesth Pain Med. 2015 Jun 22;5(3)

38.  Monteiro EMH et al Antinoceptive and anti-inflammatory activities of the sesame oil and sesamin. Nutrient. 2014 May; 6(5) 1931-1944

39.  Hsu CC  et al, Sesame oil improves functional recovery by attenuating nerve oxidative stress in a mouse model of acute peripheral nerve injury:  role of Nrf-2. J Nutr Biochem 2016 Dec;38:102-106

40.  Hsieh PF et al Sesamin ameliorates oxidative stress and mortality in kainic acid-induce status epilepticus by inhibition of MAPK and Cox-2 activation. J Neuroinflammation. 2011 May 24;8:57

41.  Cheng FC et al Neuroprotective effects of sesamin and sesamolin on gerbil brain in cerebral ischemia. Int J Biomed Sci. 2006 Sep;2(3):284-8

42.  Rauf K et al Effect of Bacopasides on acquisition and expression of morphine tolerance. Phytomedicine. 2011 Jul 15; 18(10):836-42

43.  Shahid Muhammid et al A bacosides containing Bacopa monnieri extract alleviates allodynia and hyperalgesia in the chronic constriction injury model of neuropathic pain in rats. BMC Complement Altern Med. 2017 Jun 5;17(1):293

44.  Sahoo PK et al Neuroprotective effect of Bacopa monnieri leaf extract targeted at adenosine receptor in diabetic neuropathic pain. Journal of Pharmacy Research 2010,3(8),1806-1809

45.  Kulkarni R et al Nootropic herbs (Medhya Rasayana) in Ayurveda: An update. Pharmacogn Rev. 2012 Jul-Dec; 6(12): 147-153

46.  Kumar N et al An update on Shankhpushpi, a cognition-boosting Ayurvedic medicine. Journal of Chinese Integrative Medicine: Volume 7, 2009, issue 11

47.  Bihaqi SW et al Supplementation of Convolvulus pluricaulis attenuates scopolamine-induced increased tau and amyloid precursor protein (AbetaPP) expression in rat brain. Indian Journal of Pharmacology, October 2012,Vol 44, Issue 5 pages 594-598

48.  57.  Siddiqui NA et al Neuropharmacological profile of extracts of aerial parts of Convolvulus pluricaulis Choisy in mice model.  Open Neurol J  2014:8: 11-14

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