Targeted Natural Interventions
Elevated blood glucose drives complications of diabetes, including neuropathy, via several mechanisms. For example, high glucose promotes inflammation as well as glycation, and perturbs blood flow to neurons, all of which contribute to neuropathy. Unfortunately, most conventional drug treatments aim to provide symptomatic relief without targeting these underlying mechanisms (McIlduff 2011). However, several natural interventions have been shown in studies to modulate biological pathways that underlie the development and progression of neuropathy. Thus, by taking steps to keep fasting glucose levels within the optimal range of 70 – 85 mg/dL and supplementing with natural compounds that mitigate the negative effects of excess glucose, one can ensure a robust defense against diabetic complications.
Life Extension has identified several novel strategies that can help optimize glucose control. These strategies are outlined in the Weight Loss protocol and the Diabetes protocol. Individuals with diabetic neuropathy are encouraged to review these protocols in addition to the suggestions outlined here.
Honokiol is a polyphenolic compound from the bark of the magnolia tree (Magnolia grandifolia). Magnolia bark extracts have been used traditionally as sedatives to improve sleep and relieve anxiety, and honokiol is being investigated for its potential usefulness in treating inflammatory pain (Alexeev 2012; Woodbury 2013).
Like other polyphenols, honokiol has oxidative stress-reducing and anti-inflammatory activities. In addition, it appears to cross the blood-brain barrier and interact with certain neurotransmitter receptors in the brain (Woodbury 2013; Alexeev 2012). Laboratory research shows honokiol and some of its derivatives activate certain GABA receptors (Bernaskova 2015), and may also interact with receptors for glutamate, dopamine, and serotonin, and influence acetylcholine signaling (Alexeev 2012). One form of honokiol has even been shown to stimulate cannabinoid receptors that may be involved in decreasing pain perception (Gertsch 2012).
In one study, treatment with honokiol reduced pain-related behaviors in mice in experimental models of inflammation (Lin 2009). Findings from other animal studies indicate honokiol may decrease acute inflammatory pain without causing motor or cognitive side effects, and may prevent and decrease some of the chronic pain-related changes in the brain (Woodbury 2015; Lin 2007).
Palmitoylethanolamide (PEA) is a lipid compound that occurs naturally in tissues throughout the body, including the central nervous system. It can also be found in foods such as soy lecithin, egg yolk, and peanuts (Mattace Raso 2014; LoVerme 2005). A growing body of research suggests PEA supplementation may be effective for relieving pain from a variety of causes without triggering adverse side effects (Artukoglu 2017; Paladini 2016; Gabrielsson 2016). Most of the existing preclinical research indicates that PEA works by changing the expression of certain genes and reducing inflammatory signaling, but other possible mechanisms for its analgesic effect have also been proposed, including its ability to stimulate signaling through cannabinoid receptors in the nervous system (Gabrielsson 2016; Di Cesare Mannelli 2013; Skaper 2012; Khasabova 2012).
Several clinical trials have shown that PEA can reduce pain from a broad array of causes, including diabetic neuropathy, chemotherapy-induced peripheral neuropathy, sciatic nerve compression, carpal tunnel syndrome, osteoarthritis, low back pain, failed back surgery, stroke-related nerve pain, multiple sclerosis, dental pain, chronic pelvic pain, post-herpetic neuralgia, and vaginal pain (Hesselink 2012). In an observational study of individuals with chronic pain due to a variety of conditions who were unable to control their pain with usual therapies, adding 600 mg PEA twice daily for three weeks followed by once daily for another four weeks decreased average pain intensity scores in all participants who completed the study (Gatti 2012).
In a randomized controlled trial, 636 participants with pain due to compression of the sciatic nerve received either 300 mg PEA daily, 600 mg PEA daily, or placebo in conjunction with their usual pain medications for three weeks. Both doses of PEA resulted in greater pain reduction than placebo, and the higher dose was more effective than the lower dose. In fact, those in the 600 mg group experienced more than a 50% reduction in pain scores (Keppel Hesselink 2015). In 118 patients with nerve pain, 30 days of standard treatment plus 600 mg PEA daily was more effective than standard treatment alone (Dominguez, Martin 2012). A randomized clinical trial found that 900 mg PEA daily for one week followed by 600 mg daily for one week was more effective than ibuprofen, at a dose of 600 mg three times daily for two weeks, for relieving temporomandibular joint (TMJ) pain (Marini 2012).
Micronized preparations of PEA have also been studied. Micronization results in smaller particles that may be absorbed more readily. Micronized PEA, at doses of 600–1,200 mg/day, reduced pain in subjects with diabetes- or trauma-related nerve pain, chronic pain after failed back surgery, and acute pain from tooth extraction (Cocito 2014; Paladini 2017; Bacci 2011). In a report of 100 cases of nerve pain related to spinal disorders, the inclusion of an ultra-micronized PEA supplement in pain management therapy showed promising results (Chirchiglia 2017). A meta-analysis found that women with chronic pelvic pain due to endometriosis appear to benefit from the combination of 800 mg micronized PEA daily plus 80 mg per day of polydatin, a natural free radical-reducing agent found in grapes and red wine (NIH 2017; Indraccolo 2017). In a randomized controlled trial, the combination of PEA and polydatin was more effective than placebo for reducing abdominal pain in irritable bowel syndrome patients (Cremon 2017).
Lipoic acid is a compound produced within the body that exerts a variety of beneficial effects within the body, especially in the context of glucose metabolism (McIlduff 2011). In fact, lipoic acid is an approved treatment for diabetic neuropathy in Germany (McIlduff 2011; Head 2006). In addition, it appears lipoic acid may positively influence glucose metabolism in people with diabetes (Korotchkina 2004). Important mechanisms by which lipoic acid helps combat diabetic neuropathy include inhibition of glycation and inflammation (Thirunavukkarasu 2005; Kunt 1999; Bierhaus 1997). It has also been reported that lipoic acid can protect against oxidative damage in neuronal cell culture (Bharat 2002). It also improves blood flow to nerves and allows them to use energy more efficiently (Bertolotto 2012; McIlduff 2011). In animal studies, lipoic acid has been found to prevent and even reverse nerve dysfunction caused by high blood sugar levels.
Results of clinical trials have been promising. One trial showed that 3 daily doses of 600 mg of alpha-lipoic acid over 3 weeks led to significant symptomatic improvement in 12 patients with diabetic neuropathy. In another trial, 181 patients were divided into groups receiving placebo or 600, 1200, or 1800 mg of alpha-lipoic acid daily. Significant symptomatic improvement was noted in the 1800 mg/day group in as little as one week, with the 600 and 1200 mg groups experiencing improvement by week 2 (McIlduff 2011). In both of these trials, sensations of pain and burning were alleviated. A separate study found that oral administration of 600 mg of lipoic acid daily over the course of 4 years improved neuropathic symptoms and slowed the progression of mild to moderate diabetic neuropathy (Ziegler 2011).
Other trials show that intravenous lipoic acid is also beneficial for diabetic neuropathy. One study revealed that daily intravenous administration of alpha-lipoic acid for 3 weeks is an effective treatment for diabetic neuropathy, and another trial reported that intravenous administration for 2-4 weeks was efficacious (McIlduff 2011; Han 2012).
Lipoic acid is available as a supplement in 2 forms: alpha-lipoic acid and R-lipoic acid. Evidence suggests that the sodium salt of R-lipoic acid may be more bioavailable than alpha-lipoic acid (Carlson 2007).
Capsaicin is the chemical in hot peppers responsible for their “spiciness” (Ziegler 2009). When capsaicin is applied to the skin, it stimulates some of the same nerves that signal pain and produces redness and a sensation of burning. However, after a period of time, these nerves become desensitized and no longer transmit pain stimuli, including pain from diabetic neuropathy (Webster 2011; Martini 2012). Studies have found that topical application of capsaicin, either using creams (0.075% capsaicin) or patches, is an effective treatment for diabetic neuropathy (Ziegler 2009; Webster 2011; Martini 2012). Application of a single patch containing 8% capsaicin for 12 weeks after pre-treatment with lidocaine reduced pain from diabetic neuropathy by a mean of 31% in one study (Webster 2011). Capsaicin is intriguing because some people may be able to obtain a great deal of relief from topical capsaicin. One study found that 34% of patients using a capsaicin patch experienced an average decrease in pain of 70% that persisted over the course of the 12-week trial (Martini 2012). This suggests that for some people, the use of topical capsaicin may provide powerful relief from diabetic neuropathy.
N-acetylcysteine (NAC) is a small molecule able to pass through cell membranes and serves as a precursor for the amino acid cysteine, which itself functions directly as an antioxidant and helps increase the levels of another naturally occurring antioxidant, glutathione. NAC also functions as an antioxidant on its own, and it was shown to protect neurons from oxidative damage (Kamboj 2010; Sakai 2001). In addition, NAC has been shown to suppress the formation of AGEs (Nakayama 1999). Multiple studies on animal models of diabetic neuropathy found that NAC prevents neuron death and protects against nerve damage (Kamboj 2010; Love 1996; Sagara 1996; Head 2006).
Acetyl L-Carnitine (ALC) and L-Carnitine
Carnitine is an amino acid-like compound important for mitochondrial energy production (Evans 2008). Some of the interest in carnitine’s role in diabetic neuropathy stems from evidence that diabetics with complications, including diabetic neuropathy, have lower blood levels of free and total carnitine than diabetics without complications; this finding supports previous findings from animal studies (Tamamoguillari 1999). As a result, ALC and L-carnitine have been studied as potential treatments for diabetic neuropathy. Carnitine supplementation may help combat carnitine deficiency, improve insulin resistance, allow cells to use glucose more efficiently, help regenerate damaged nerve fibers, or help damaged neurons transport intracellular components more effectively (Evans 2008).
Multiple human trials have been conducted on the effects of carnitine supplementation on diabetic neuropathy. One study found that L-carnitine (2 g daily for 10 months) improves nerve conduction velocity, which is impaired in diabetic neuropathy (Ulvi 2010). Studies done on ALC found that it reduced pain, improved vibration sensation in the legs, and increased nerve regeneration in patients suffering from diabetic neuropathy (Bansal 2006; Sima 2005; Adriaensen 2005; Evans 2008; De Grandis 2002). Carnitine supplements may also aid in treating the autonomic neuropathy caused by diabetes; a study done on an animal model found that ALC reduced the cardiovascular signs of diabetic autonomic neuropathy (Giudice 2002).
B-vitamins are a family of vitamins that play many roles in the human body, especially in cellular energy generation and nervous system function (Selhub 2000).
Thiamine (B1) and benfotiamine. A lack of thiamine can directly cause neuropathy (Head 2006). Early research found that thiamine could be used to treat painful diabetic neuropathy. Benfotiamine is a fat-soluble derivative of thiamine that is more readily absorbed by the digestive tract (Sanchez-Ramirez 2006).
Benfotiamine may modulate several pathways that contribute to diabetic neuropathy: the formation of AGEs, the protein kinase C pathway, and damaging changes that can occur within cells due to high glucose levels (Varkonyi 2008; Balakumar 2010). It may also help prevent vascular problems that contribute to neuropathy (Stracke 2008). Multiple clinical trials have examined the effects of benfotiamine on diabetic neuropathy (Stracke 2008; Haupt 2005; Winkler 1999; Head 2006) and have found that, particularly at doses ranging from 300 to 600 mg daily, it was able to relieve diabetic neuropathy symptoms, especially pain.
Vitamin B12. Vitamin B12 is critical for the function of the nervous system, and a lack of it can cause significant peripheral neuropathy (Head 2006). In addition, people with diabetic neuropathy often have high levels of the blood vessel-damaging compound homocysteine, which can be elevated in the presence of low vitamin B12 levels (Fahmy 2010). Researchers have also examined the potential benefits of vitamin B12 supplementation in treating diabetic neuropathy; the form of vitamin B12 known as methylcobalamin, which has an affinity for nerve tissue, has been studied extensively in this regard (Mizukami 2011). Studies in animal models of diabetic neuropathy have found that methylcobalamin may mitigate the damage caused by diabetic neuropathy, possibly by modulating the protein kinase C signaling pathway or activating chemical signals that help nerves survive and regenerate (Mizukami 2011; Okada 2010; Jian-Bo 2010).
Clinical studies have also yielded promising results. A combination of 2 mg of methylcobalamin, 3 mg of L-methylfolate (a form of folic acid), and 35 mg of pyridoxal 5’-phosphate (a form of vitamin B6) was found in multiple clinical trials to improve symptoms of neuropathy and help maintain the health of small nerves in the lower extremities (Jacobs 2011; Walker 2010; Fonseca 2013). Combinations of these three nutrients have also been found to help reduce hospitalization and medical care costs in people with diabetic neuropathy (Wade 2012). Studies looking at methylcobalamin alone have also been encouraging. Both oral methylcobalamin (1500 mcg daily) and injected methylcobalamin (2000 mcg daily) were found to improve numbness, reflexes, sensitivity to vibration, pin-prick stimulation, gait, and pain (Talaei 2009; Dominguez 2012). One study even found that methylcobalmin was more effective than nortriptyline, an antidepressant commonly used to treat diabetic neuropathic pain (Talaei 2009).
Folate and vitamin B6. Much like methylcobalamin, vitamin B6 is important for nerve function, while folate may help improve the function of blood vessels that supply the nerves (Fonseca 2013). As discussed previously, derivatives of folate and vitamin B6 have been tested in clinical trials, along with methylcobalamin, and showed positive results (Jacobs 2011; Walker 2010; Fonseca 2013).
Vitamins C and E
Research has found that diabetics have low levels of vitamin C; and this appears to be a result of the disease itself, not of decreased dietary intake of vitamin C (Sinclair 1994). Another piece of evidence pointing to the importance of vitamin C is that people with diabetic neuropathy have elevated levels of “reduced” vitamin C, which is vitamin C that has already been used by the body. This suggests that diabetic neuropathy places an extra strain on the body’s stores of vitamin C. Reduced levels of vitamin E are also seen in people with diabetic neuropathy and animals with diabetes (Ziegler 2004). Vitamin E supplementation alone has been found to improve signs of peripheral neuropathy (Martinello 1998) and may also improve nerve conduction in people with type 2 diabetes (Tutuncu 1998). In addition, treatment with vitamins C and E has been found to be beneficial in both animal models of diabetic neuropathy (Sharma 2009) and one clinical trial (Farvid 2011).
One study found that diabetics have lower levels of zinc, chromium, and manganese in their hair and blood, suggesting that deficiencies of these nutrients may be associated with diabetic neuropathy (Gul Kazi 2008). Moreover, diabetes is the most common disease that causes secondary magnesium deficiency, with 25-30% of type 1 diabetics and 13.5-47.7% of type 2 diabetics having magnesium deficiency (Rondon 2010). In rat models of diabetes, administration of oral magnesium or a magnesium-releasing compound helped protect nerves from diabetic neuropathy (Hosseini 2010; Rondon 2010). A clinical trial also found that 500 mg of oral magnesium supplementation daily for 5 years slowed the progression of diabetic neuropathy in humans (De Leeuw 2004). Zinc has also shown promise as a treatment for diabetic neuropathy. Clinical studies have found that zinc supplementation helps improve glycemic control and also reduces the severity of diabetic neuropathy (Jayawardena 2012; Gupta 1998; Hayee 2005). Finally, a clinical study found that supplementation with micronutrients, including zinc and magnesium, together with vitamins C and E, with or without vitamins from the B group, for 4 months improved signs of diabetic neuropathy (Farvid 2011).
Omega-3 fatty acids
Omega-3 fatty acids have historically been studied for their effects on vascular disease, as diets high in omega-3 fatty acids are associated with a lower risk of heart disease. While data from clinical trials on the benefits of omega-3 fatty acids specifically in the context of diabetic neuropathy is lacking, several animal models of diabetic neuropathy have suggested a potential role for these important fats (De Caterina 2007). One theory is that diabetic neuropathy is associated with lower levels of omega-3 fatty acids in the membranes of affected nerves. Two different studies on animal models of diabetic neuropathy found that supplementation with omega-3 fatty acids improved signs of diabetic neuropathy (Gerbi 1999; Coste 2003).
Curcumin, a yellow pigment found in the plant Curcuma longa, is a major component of turmeric (Sharma 2006). Curcumin possesses anti-inflammatory properties (Joshi 2013). Evidence suggests that curcumin may modulate pain sensations via decreasing levels of a free radical called nitric oxide and suppressing the inflammatory mediator TNF-α (Sharma 2006). As a result, it may interfere with pain signaling from nerves damaged by diabetic neuropathy as well as prevent oxidative damage to nerves (Lakshmanan 2011).
The main evidence for the use of curcumin in diabetic neuropathy stems from preclinical studies. In an animal model of diabetic neuropathy, curcumin has been found to reduce oxidative damage in the nerves from the central and peripheral nervous systems (Acar 2012; Lakshmanan 2011). Curcumin administration also reduced cell death in animal models of diabetic neuropathy (Cao 2010; Lakshmanan 2011). Additional studies have found that curcumin reduced inflammation and sensitivity to pain in animal models of this disease (Sharma 2007; Sharma 2006; Kulkarni 2010; Attia 2012; Li 2013).
Vitamin D deficiency was reported to be an independent risk factor for the development of diabetic neuropathy in peripheral nerves (Shehab 2012), and supplementation may be helpful for some diabetics with neuropathy. Vitamin D deficiency is present in people with both type 1 and type 2 diabetes, and it is more common in diabetics who have significant symptoms of neuropathy and reduced pain threshold (Bell 2012). A study that enrolled adults with diabetes reported that vitamin D insufficiency, defined as levels below 30 ng/mL, is associated with worse self-reported diabetic neuropathy symptoms, and this association persisted even after adjustments were made for several variables, such as obesity or diabetes duration and control (Soderstrom 2012). Two different papers have been published on the effects of vitamin D supplementation in people with diabetic neuropathy and vitamin D deficiency. One study on 51 patients with type 2 diabetes found that vitamin D supplementation reduced reported pain levels by almost 50% and suggested that vitamin D could be used as an “analgesic” in patients with pain caused by diabetic neuropathy (Lee 2008). The second is a case report of a patient with vitamin D deficiency and diabetic neuropathy that was severe enough to require use of narcotic pain medications to control his symptoms. This individual gained significant pain relief from vitamin D supplementation, suggesting that taking vitamin D may provide substantial relief from diabetic neuropathy symptoms (Bell 2012). Life Extension suggests that most people strive to maintain 25-hydroxyvitamin D levels of 50 – 80 ng/mL.
Resveratrol and Grape Seed Extract
Resveratrol is a natural phytochemical found in grapes, red wine, and Japanese knotweed. In an animal model of diabetes, resveratrol was shown to protect against neuropathy as a result of its ability to inhibit inflammation as well as reduce oxidative stress and DNA damage (Kumar 2007; Kumar 2010). In another preclinical study, resveratrol was found to decrease sensitivity to pain when combined with insulin (Sharma 2007).
Compounds derived from grape seed called proanthocyanidins were shown, in an animal model of diabetes, to improve the speed of conduction in motor nerves and modulate pain sensation; they also decreased the loss of the protective sheath known as myelin, which surrounds nerves. In addition, they decreased the production of AGEs, which suggests they also decreased the oxidative damage to the nerves that occurs as part of diabetic neuropathy (Cui 2008).
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This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.
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