CPE Monthly: Health Benefits of Nettles - Today's Dietitian Magazine

August/September 2020 Issue

CPE Monthly: Health Benefits of Nettles
By Ginger Hultin, MS, RDN, CSO
Today’s Dietitian
Vol. 22, No. 7, P. 54

Suggested CDR Performance Indicators: 8.1.1, 8.1.4, 8.3.1
CPE Level 2

Take this course and earn 2 CEUs on our Continuing Education Learning Library

Stinging nettles can cause extreme dermatological discomfort if encountered on a hike in the woods, but these herbaceous plants that grow in regions around the world may have some important health benefits if prepared safely for use in food or supplements.

Officially called Urtica diocia or Urtica urens, the plant commonly known as nettles grows in both temperate and tropical climates and can be identified by its pointed green leaves and white or yellow flowers. In the United States, nettles exist in every state except Hawaii and Arkansas.1,2

Nettles can be incorporated into food and beverage preparations and used in manufacturing of bath and body products, and both the root and leaf are used for medicinal purposes in tea, tincture, or supplement form.2 They have a long history of medicinal and textile use. Research on health benefits developed in the 20th century, but some estimates suggest nettles have been used for more than 2,000 years for textiles.3 Studies show nettles were used in woven plant fiber textiles in the Bronze Age in Europe. Before these studies, it was believed these textiles mostly were woven from flax and hemp, but nettles since have been discovered as an important part of textile production of that time.4 Nettles still are components of modern fabric manufacturing and sustainable textiles. They’re an ingredient in animal fodder and used in biodynamic agriculture, various industries, and in hair and skin products and cosmetics.5

Nettles can be eaten as cooked leaves like a vegetable or prepared in a tea, and often are used in supplement form to treat many conditions, including urination disorders and benign prostatic hypertrophy (BPH), high blood sugar, osteoarthritis, circulation, blood pressure, cancer, and allergic rhinitis. They’re also used topically as an astringent to soothe muscle pain and treat hair loss.2 Common medicinal nettle preparations include crude dried powder, dry extract, or herbal tea.3

Fresh nettles contain unicellular stinging hairs on the stems and leaves that cause dermatitis upon contact. The tips come off when touched, and the hair turns into a needle that injects a stinging liquid into its new host. In this way, the mechanism of dermatitis is both biochemical and mechanical. The liquid contains compounds that cause allergic reactions and discomfort including acetylcholine, histamine, and serotonin.1,3 When hiking, walking, or gardening in areas where nettles grow, individuals must use caution and avoid skin contact to escape this unpleasant experience, which includes an immediate stinging and burning sensation on the skin.1 Care also must be taken when harvesting nettles for culinary use.

This continuing education course reviews the health benefits of nettles and shares strategies clients can use to incorporate them into their diets for nutrition and health.

Nutrients and Dietary Uses of Nettles
Nettles can be prepared for consumption in a manner that eliminates the stinging properties of the leaves so they can be used. Many of their health properties are linked to antioxidant compounds in various parts of the plant. Nettle root contains lectins, polysaccharides, sterols, lignins, and fatty acids. Nettle leaf contains nutrients including carotene, vitamins C and K, potassium, calcium, iron, zinc, phosphorus, magnesium, alpha-linolenic acid, antioxidant flavonoids, and phenolic compounds. The concentrations of vitamin C and carotene it contains are similar to those found in other leafy greens including spinach.2,3 For that reason, nettles commonly are used in recipes in much the same way as cooked spinach. Nettles contain antioxidant flavonoids, such as quercetin, kaempferol, and rutin, which may contribute to the anti-inflammatory and anticancer potential in nettles.3

Health Benefits
A variety of constituents may contribute to the health benefits of nettles. For example, improvements to allergic rhinitis have been attributed to the antioxidant quercetin. Lectin agglutinin may provide anticancer properties. Polysaccharides may reduce inflammatory markers including interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha).2 Prostate health improvement may come from the beta-sitosterol in nettles. This and osteoarthritis are among the most studied uses for nettles.2,6

Urinary Tract Support and BPH
Nettles are used to treat a variety of urinary tract issues and contain many compounds that aid in treating BPH. BPH is a common urologic condition often associated with aging. The prostate becomes enlarged, squeezing the urethra and making urination difficult, urgent, or frequent. Treatment options include lifestyle changes, surgical treatment, and medications including adrenoceptor antagonists (alpha-blockers), 5-alphareductase inhibitors, phosphodiesterase type 5 inhibitors, antimuscarinics, beta-3-adrenoceptor agonists, vasopressin analogs, and phytotherapeutic agents such as nettles. Some researchers state that nettles should be used in patients with mild to moderate grades of the disease, and that medications or surgery may be needed if it worsens.7

Clinical studies on nettle root extract show a significant improvement of BPH symptoms in humans.3,8-10 One of the most researched effects of nettles is improved symptoms of BPH including increased urine flow.2,10 Some studies combine nettle root with other herbs such as saw palmetto to treat this condition.2,11 Nettles contain the plant sterol beta-sitosterol, which has been used to treat BPH and improve symptoms of reduced urinary flow.6 Researchers hypothesize that beta-sitosterol could inhibit 5-alpha-reductase, an enzyme that converts testosterone to its active form dihydrotestosterone. The results of an animal study found beta-sitosterol similarly effective, but less potent, than finasteride, a common medical treatment for BPH.6 Nettle root extract has been shown to reduce production of estrogen through aromatase inhibition, decreasing the conversion of androgens to estrogen, which also can help reduce BPH.3,10

In a study in International Urology and Nephrology, researchers completed a randomized, double-blinded, placebo-controlled crossover clinical trial using nettle root extract combined with saw palmetto or placebo for 96 weeks in 257 elderly men with lower urinary tract symptoms caused by BPH. Using the International Prostate Symptoms Score questionnaire, the self-rated score of the intervention was reduced by 53% from the start of the study (p<0.001). In addition, peak and average urinary flow increased 19% (p<0.001), and residual urine volume decreased 44% (p=0.03). In this study, the herbal preparation in capsules showed good tolerability over long-term administration and high acceptance, with very few premature withdrawals.12 Of those who did withdraw, the majority had urinary system problems, including renal calculus, followed by respiratory system disorders and cardiac conditions. Keep in mind that this was a combination treatment, including saw palmetto, which research has shown is helpful in treating BPH and other prostate conditions, so there could be confounding factors when intervening with more than one herb.2,11

In another prospective, randomized, double-blinded, placebo-controlled crossover study of 620 patients, both groups were on medication; one group added nettle extract while the other group received a placebo. Five hundred fifty-eight patients completed the study. At the end of the six-month trial, 81% of 287 patients in the nettles plus medication group reported an improvement in lower urinary tract symptoms compared with 16% of 271 patients in the placebo group (p<0.001). The International Prostate Symptom Score went from 19.8 to 11.8 with nettles compared with 19.2 to 17.7 with placebo (p=0.002). Peak flow rates improved by 3.4 mL/s for placebo recipients and by 8.2 mL/s for those treated with nettles (p<0.05). In the nettles intervention group, postvoid residual urine volume decreased from an initial value of 73 to 36 mL (p<0.05). A modest decrease in prostate size was observed in the nettles group (40.1 cc to 36.3 cc; p<0.001), and there was no change in prostate volume at the end of the study in the placebo group. At the 18-month follow-up, only patients who continued therapy with medication and nettles showed improved treatment values. Neither group displayed any side effects.9

In Phytomedicine, Chrubasik and colleagues stated that using nettle root for BPH treatment is considered safe because toxicity and risk of adverse events are very low; nettle root is a natural food product with few interactions with medical conditions or medications.10

Anti-Inflammatory Relief for Osteoarthritis
Nettles are used orally and topically to relieve osteoarthritis-related pain. Some research suggests that adding nettles as a treatment for osteoarthritis may decrease the need for nonsteroidal anti-inflammatory drugs, the most common treatment for pain relief for this condition.2

Research in Phytomedicine Journal found that the methanolic extract of the flowering portions of nettles showed considerable anti-inflammatory activity equal to anti-inflammatory agent celastrol, used to treat rheumatoid arthritis.13

Another study in Pharmaceutical Biology found that 300 mg/kg nettle leaf extracted with solvents and consumed orally exhibited anti-inflammatory activity comparable to the nonsteroidal anti-inflammatory drug indomethacin.14

Nettles decrease the inflammatory response by inhibiting the biosynthesis of arachidonic acid cascade enzymes including cyclooxygenases COX-1 and COX-2, reducing biosynthesis of prostaglandins and thromboxanes, and reducing transcription factor nuclear factor-kappa-B (NF-kappa-B), which helps regulate cytokines such as TNF, interleukin-1, interleukin-2, IL-6, and interleukin-8.3,15,16 Studies have shown that nettle extracts inhibit the expression of these inflammatory cytokines as well as eicosanoid formation in stimulated peripheral blood cells. A German study by Riehemann and colleagues from the University of Tübingen concluded that nettle extract’s inhibitory effect on these inflammatory cascades is demonstrated in several cell types including T-cells, macrophages, and fibrosarcoma and epithelial cells. This study also showed that nettles interfered with a common target in the NF-kappa-B pathway.16

A small study of 42 patients with osteoarthritic knee pain in Complementary Therapies in Medicine found that pain subscale score was reduced in the nettle intervention group by a mean reduction in pain score of 1.7 (95% confidence interval) and 1.6 in the control group. Participants in this study reported they sought the nettle treatment because it was “natural,” indicating an ongoing interest in natural medicine to treat common ailments.17

Allergic Rhinitis
Studies have shown that nettles provide subjective improvement in symptoms of allergic rhinitis due to its anti-inflammatory properties.2,15,18 Nettles contain an alkaloid compound called synephrine used in traditional Chinese medicine to treat seasonal allergies and other inflammatory disorders.18

In vitro studies show antagonist activity against the histamine-1 receptor and the inhibition of mast cell tryptase, which prevents degranulation and release of proinflammatory mediators responsible for allergy symptoms. Nettle extract inhibits prostaglandin formation by inhibiting the proinflammatory enzymes COX-1, COX-2, and hematopoietic prostaglandin D2 synthase.15 Study participants typically use 300 mg nettle leaf extract three to seven times daily at the first sign of symptoms.2

In a randomized, double-blinded, placebo-controlled clinical trial by Bakhshaee and colleagues on the efficacy of nettle root for allergic rhinitis, 74 patients took a 150-mg once-daily supplement or placebo for four weeks. Researchers measured signs and symptoms, eosinophil percentage on nasal smear, serum IgE, and interleukin-4, interleukin-5, and interferon-gamma (IFN-gamma) levels. Participants who took the intervention dose experienced a significant reduction in nasal smear eosinophil count (p<0.01), although there were no significant changes in inflammatory markers. Improvement in clinical symptom severity was reduced significantly in both intervention and placebo groups. Researchers hypothesized that the reason the placebo group experienced decreased symptom severity was because IFN-gamma, a cytokine produced by T and natural killer cells, significantly declined, which could be temporary based on treatment. Researchers stated that, in time, the patients again could experience progress of allergic rhinitis.18

Although there’s some evidence that nettles aid in allergic rhinitis, more research is needed to better understand the potential efficacy and the necessary dosages.

Blood Pressure and Circulatory Treatment
Nettles have several nutritional attributes that benefit the cardiovascular system. They’ve been used in traditional and natural medicine to calm inflammation and improve markers for cardiovascular health including blood pressure and blood lipids.19 The high potassium content of nettles could help support healthy blood pressure, and the iron content combined with a natural source of vitamin C could increase bioavailability, helping to treat anemia.3 Studies in rats and guinea pigs have found both hypotensive effects and vasorelaxing effects mediated by the release of endothelial nitric oxide (NO) and the opening of potassium channels.20

In one double-blinded, randomized, placebo-controlled clinical trial involving 50 women with type 2 diabetes, researchers examined the effects of nettle supplementation on blood lipids, hepatic enzymes, and NO levels, finding that an eight-week treatment yielded a decrease in cardiovascular risk factors. In the intervention group, consuming 5 mL nettle extract in three portions per day after meals decreased fasting blood glucose and increased HDL cholesterol. There was a significant decrease in glutamic pyruvic transaminase, also known as liver enzyme alanine aminotransferase (p<0.001), and a significant increase in NO (p<0.001) and superoxide dismutase (p<0.001).19 Note that there were limitations to this study including lack of precise control of diet- and exercise-related lifestyle changes, so it’s difficult, as with many studies, to understand the exact role of the nettle intervention.

More human studies are needed to better assess the use of nettles for reduction in blood pressure and circulatory treatment, including improved blood lipid markers in patients with and without diabetes.

Blood Sugar Control
Human and animal studies have shown that nettles have a protective effect against hyperglycemia by decreasing fasting blood glucose levels.3,19 Nettles also are thought to increase insulin secretion by the islets of Langerhans in the pancreas. Researchers hypothesize that the mechanisms behind this are connected to the flavonoids in nettles, including tannins and carotenoids exhibiting antioxidant properties.19

A 2013 randomized double-blinded placebo-controlled study by Kianbakht and colleagues found that taking 500 mg nettle extract three times daily for three months decreased fasting blood glucose by 32.4% and HbA1c by 18.1% compared with baseline measures in patients with uncontrolled, advanced type 2 diabetes. The 107 patients in this study had fasting glucose and HbA1c levels above 200 mg/dL, and 8% were resistant to conventional oral antihyperglycemic drugs (eg, glibenclamide, metformin, gliclazide, acarbose, pioglitazone, and repaglinide) and needed insulin therapy but refused to take it. The researchers concluded that nettles may improve the efficacy of conventional oral antihyperglycemic drugs in this patient population. They stated that the antihyperglycemic efficacy of nettles could be greater than conventional oral antihyperglycemic drugs for patients whose medications no longer are enough to control type 2 diabetes.21 Studies suggest that the hypoglycemic effects of nettle leaf extract are connected to the inhibition of the intestinal absorption of glucose that has been found in animal studies.3,22 Patients should work with their medical team to better understand adding nettles or other supplements in addition to or in replacement of medications.

In a study by Dar and colleagues in Pharmaceutical Biology, nettle extract significantly reduced blood glucose levels by 67.92% in one hour during a glucose tolerance test in rats (p<0.001). The authors hypothesized that the major bioactive molecules in the extract exhibit insulinlike effects or stimulate the pancreatic beta cells to produce insulin, lowering blood glucose.14 A small randomized double-blinded placebo-controlled clinical trial including 50 people with type 2 diabetes was conducted over the course of eight weeks by Namazi and colleagues. They found that 100 mg/kg nettle extract yielded a significant decrease (p<0.05) in inflammatory markers IL-6 and high-sensitivity C-reactive protein (hs-CRP) in 25 intervention patients compared with the placebo group.23

Nettles may help control blood sugar by decreasing blood glucose, increasing insulin secretion, and reducing inflammation in people with type 2 diabetes.2,3,21-23 Because of this, people with diabetes should be cautious about taking nettles as a supplement, especially if they’re being treated with hypoglycemic medications, as the outcomes of the supplement plus these medications could compound. Clients always should talk with their dietitians, physicians, or pharmacists before taking blood sugar–lowering supplements. At this time, research on nettles for treating diabetes is inconclusive, and therefore shouldn’t be recommended as a replacement for traditional dietary and lifestyle changes and/or medication.

Anticancer Properties
In addition to its blood glucose–lowering capabilities, nettles contain compounds with anticancer properties including lectins such as agglutinin, polysaccharides, and TNF-alpha, flavonoids such as quercetin, and beta-sitosterol.2 Polysaccharides’ ability to decrease inflammatory markers could be one reason nettles have been shown to exhibit anticancer properties.

Quercetin has been shown to exhibit antitumor activity against prostate cancer specifically.3,6 Studies have shown both in vivo and in vitro antiprostate cancer effects of nettles. A German study by Konrad and colleagues found that nettle extract exhibited significant antiproliferative effects on human prostatic epithelial cells (p<0.05). The researchers didn’t observe any cytotoxic effects and concluded that nettles contain biologically relevant compounds to treat prostate cancer.24

There are also in vivo studies on the antioxidant and apoptotic effects of nettle extract on human breast cancer cells. A study by Fattahi and colleagues found that nettle extract showed antioxidant effects with a correlation coefficient of r2=0.997. The researchers concluded that the antiproliferative activity correlated with increased apoptosis (ie, programmed cell death). Researchers observed significant growth inhibition of breast cancer cells treated with nettle extract, indicating a need for more research on the positive effects nettles could have on breast, prostate, and other types of human cancers.25

Autoimmune Disease Properties
Because of the potential anti-inflammatory and analgesic properties of nettles and nettle extract, these compounds commonly are used in topical preparations to treat autoimmune diseases including rheumatoid arthritis. Studies on autoimmune diseases and nettles largely have been conducted on animals, namely mice, which have shed light on the potential for use in humans based on efficacy for pain relief. One study on four groups of six mice each with rheumatoid arthritis found that the group fed a nettle extract gel had a 55% reduction in edema compared with a 53% reduction in the control group after 24 hours. The researchers concluded that the nettle extract gel provided excellent analgesic effects for treating pain.26

There’s research on the use of nettles in treating human patients with inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease. In a double-blinded placebo-controlled study of 65 patients with IBD, the 32 participants in the nettles group, who were administered 400 mg nettle extract three times daily for 12 weeks, experienced a reduction in serum hs-CRP inflammatory markers (p=0.012) and significant reduction in platelet count (p=0.023).27

Researchers in both studies concluded that nettles may be an appropriate and safe adjunctive treatment for some inflammatory autoimmune diseases.26,27 Because of the limitations in research at this time, larger, well-designed human studies are needed to further assess safety and efficacy of nettles for these conditions.

Safety
When used appropriately, oral administration of nettles has been shown to be safe over the long term. Nettle root has been safely used for up to two years in some studies and in oral doses up to 18 g per day.2,3

Though generally well tolerated, potential side effects of nettle use include gastrointestinal issues including constipation and diarrhea. If fresh, unprocessed nettles are encountered topically, they rapidly cause dermatologic effects including stinging, itching, and rash.2

Using nettles orally as a vegetable or tea or medicinally likely is unsafe during pregnancy, as nettles may contain compounds that act as abortifacients. Clients should use caution during lactation, as there’s insufficient information available on nettles’ safety.2

There are some potential drug-nutrient interactions involving nettles. Because of their potential antihypertensive and blood sugar–lowering effects, there may be moderate interactions with antihypertensive or antidiabetes drugs or supplements. There also may be interactions with central nervous system depressants, lithium, and warfarin.2 Clients should be advised to discuss the use of nettles in extract or supplement form with their doctors or pharmacists to ensure safety.

Culinary Uses
Nettles can be harvested carefully to prevent skin contact and used in a variety of culinary preparations. When cooking with fresh nettles, use thick gloves to avoid contact between nettles and bare skin. Some experts suggest picking only the top four to five leaves from a nettle plant and avoiding flowering plants, as they become coarse.28 Rather than harvesting nettles yourself, inquire about nettles at a natural grocer or farmers market. Fresh nettles can be found in season in spring, but they’re also available dried or frozen. Once they’re cooked, dried, or crushed, they lose their stinging properties.

Clients can use nettles in the same manner as spinach to fill pasta such as shells, tortellini, ravioli, cannelloni, or manicotti. They can use nettles in egg dishes such as shakshuka or sauté them on their own with olive oil or butter, salt, pepper, and garlic, if desired. Nettles commonly are used as a substitute for basil in pesto and can be used to make a green soup or steeped in tea.28 Commercially prepared nettle tea can be found at natural food stores or in the tea section at grocery stores.

Putting It Into Practice
Clients, especially those interested in natural remedies or foraging for their own food, may ask dietitians about the culinary or medicinal uses of nettles. Dietitians can respond to clients’ questions by providing evidence-based information about this food.

Studies show that nettles may lower blood pressure and blood sugar, reduce inflammation, improve BPH, relieve arthritis pain and symptoms of allergic rhinitis, and help fight some cancers, though research is still emerging. Research on their use for most of these conditions comes from small human studies, animal studies, or in vivo exploration, so specific recommendations regarding dosing and efficacy are unknown. Clients should work with their medical teams to ensure that taking nettles, especially in supplement or extract form, won’t interfere with their medical conditions or cause interactions with other supplements or prescribed medications.

RDs can educate clients interested in cooking with nettles on how to procure and process them safely and how to include them in the diet.

— Ginger Hultin, MS, RDN, CSO, is an integrative nutrition specialist and health writer in Seattle. She’s a past chair of the Vegetarian Nutrition Dietetic Practice Group, past president of the Chicago Academy of Nutrition and Dietetics, and owner of Champagne Nutrition LLC, a concierge nutrition practice.

Learning Objectives
After completing this continuing education course, nutrition professionals should be better able to:
1. Evaluate the nutritional composition of nettles.
2. Distinguish three potential health benefits of nettles.
3. Assess potential safety considerations when using nettles in the diet or supplement form.

CPE Monthly Examination

1. Nettle leaves predominantly contain which type of fatty acids?
a. Alpha-linolenic acid
b. Stearidonic acid
c. Gamma-linolenic acid
d. All omega-3 fatty acids

2. Nettle leaves contain which of the following flavonoids?
a. Resveratrol and anthocyanins
b. Quercetin, kaempferol, and rutin
c. Genistein, daidzein, and glycitein
d. Catechins and epicatechin gallate

3. In a 2013 study by Kianbakht and colleagues, taking 500 mg nettle leaf extract three times daily for three months affected blood sugar in which of the following ways?
a. It decreased fasting blood glucose by 32.4% and HbA1c by 18.1% when compared with baseline in patients with type 1 diabetes.
b. It decreased fasting blood glucose by 21.4% and HbA1c by 8.1% when compared with baseline in patients with uncontrolled, advanced type 2 diabetes.
c. It had no statistically significant effect on blood glucose or HbA1c in patients with type 2 diabetes.
d. It decreased fasting blood glucose by 32.4% and HbA1c by 18.1% when compared with baseline in patients with uncontrolled, advanced type 2 diabetes.

4. What dose of nettle leaf extract is used to treat allergic rhinitis in studies?
a. 3,000 mg once daily at the first sign of symptoms
b. 300 mg once daily at the first sign of symptoms
c. 300 mg three to seven times daily at the first sign of symptoms
d. 300 mg three to seven times daily when symptoms become severe

5. Nettle extract has been shown in animal studies to have what effect on arthritis?
a. It performs equally well as some anti-inflammatory medications.
b. It outperforms most anti-inflammatory medications.
c. It matches the properties of medication when used in conjunction with other herbs.
d. It needs to be combined with other herbs to have a significant effect.

6. The anti-inflammatory pathways that nettles help target include which of the following?
a. Peptidoglycan or lipoteichoic acid
b. Lymphotoxin-alpha and procalcitonin
c. Superoxide dismutase and nitric oxide
d. Transcription factor nuclear factor-kappa-B

7. Which of the following do researchers suggest is true regarding nettles’ safety?
a. Consumers should use caution because nettles often cause adverse side effects.
b. Toxicity and risk of adverse events are very low.
c. There isn’t enough information to determine whether using nettles is safe or could produce toxic effects.
d. Culinary use of nettles is safe, but nettle extract has been shown to cause adverse events.

8. What are the effects of bare-skin contact with a stinging nettle plant?
a. Allergic rhinitis including sneezing and itchy, watery eyes
b. Delayed onset of atopic dermatitis and skin bruising
c. Rapid onset of symptoms including burning and stinging followed by a rash on the skin
d. Visible burrs causing burning and stinging sensations of the skin

9. What’s the best way to harvest and prepare nettles to use in recipes?
a. Wear thick gloves and freeze the nettles to reduce stinging properties.
b. Wear thick gloves and boil, crush, or dry the nettles before consuming.
c. When picking leaves with bare hands, avoid touching the bottom, where the irritants are.
d. Pick them quickly because human skin can withstand minimal exposure to the stinging properties of nettles.

10. In which of the following ways might nettles provide cardiovascular benefits?
a. They contain compounds that mimic blood pressure–lowering medication.
b. The vitamin D and calcium micronutrient content balance within the leaves supports lower blood pressure.
c. Nettles contain unique antioxidants that cause hypotension, lowering blood pressure.
d. Nettles’ high potassium content combined with vitamin C supports blood vessel health.

References
1. Cummings AJ, Olsen M. Mechanism of action of stinging nettles. Wilderness Environ Med. 2011;22(2):136-139.

2. Nettles. Natural Medicines Database website. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=664. Updated May 4, 2018. Accessed July 6, 2018.

3. Said AAH, Otmani ISE, Derfoufi S, Benmoussa A. Highlights on nutritional and therapeutic value of stinging nettle (Urtica dioica). Int J Pharm Pharm Sci. 2015;7(10):8-14.

4. Bergfjord C, Mannering U, Frei KM, et al. Nettle as a distinct Bronze Age textile plant. Sci Rep. 2012;2:664.

5. Pinelli P, Ieri F, Vignolini P, Bacci L, Baronti S, Romani A. Extraction and HPLC analysis of phenolic compounds in leaves, stalks, and textile fibers of Urtica dioica L. J Agric Food Chem. 2008;56(19):9127-9132.

6. Cabeza M, Bratoeff E, Heuze I, Ramírez E, Sánchez M, Flores E. Effect of beta-sitosterol as inhibitor of 5 alpha-reductase in hamster prostate. Proc West Pharmacol Soc. 2003;46:153-155.

7. Morgia G, Privitera S. Phytotherapy in benign prostatic hyperplasia. In: Morgia G, Russo GI, eds. Lower Urinary Tract Symptoms and Benign Prostatic Hyperplasia: From Research to Bedside. Cambridge, MA: Academic Press; 2018:135-175.

8. Schneider T, Rübben H. Stinging nettle root extract (Bazoton-uno) in long term treatment of benign prostatic syndrome (BPS). Results of a randomized, double-blind, placebo controlled multicenter study after 12 months. Urologe A. 2004;43(3):302-306.

9. Safarinejad MR. Urtica dioica for treatment of benign prostatic hyperplasia: a prospective, randomized, double-blind, placebo-controlled, crossover study. J Herb Pharmacother. 2005;5(4):1-11.

10. Chrubasik JE, Roufogalis BD, Wagner H, Chrubasik S. A comprehensive review on the stinging nettle effect and efficacy profiles. Part II: urticae radix. Phytomedicine. 2007;14(7-8):568-579.

11. Saw palmetto. Natural Medicines Database website. https://naturalmedicines.therapeuticresearch.com/databases/food,-herbs-supplements/professional.aspx?productid=664. Updated August 8, 2018. Accessed August 26, 2018.

12. Lopatkin N, Sivkov A, Schläfke S, Funk P, Medvedev A, Engelmann U. Efficacy and safety of a combination of Sabal and Urtica extract in lower urinary tract symptoms — long-term follow-up of a placebo-controlled, double-blind, multicenter trial. Int Urol Nephrol. 2007;39(4):1137-1146.

13. Johnson TA, Sohn J, Inman WD, Bjeldanes LF, Rayburn K. Lipophilic stinging nettle extracts possess potent anti-inflammatory activity, are not cytotoxic and may be superior to traditional tinctures for treating inflammatory disorders. Phytomedicine. 2013;20(2):143-147.

14. Dar SA, Ganai FA, Yousuf AR, Balkhi MU, Bhat TM, Sharma P. Pharmacological and toxicological evaluation of Urtica dioica. Pharm Biol. 2013;51(2):170-180.

15. Roschek BJ Jr, Fink RC, McMichael M, Alberte RS. Nettle extract (Urtica dioica) affects key receptors and enzymes associated with allergic rhinitis. Phytother Res. 2009;23(7):920-926.

16. Riehemann K, Behnke B, Schulze-Osthoff K. Plant extracts from stinging nettle (Urtica dioica), an antirheumatic remedy, inhibit the proinflammatory transcription factor NF-kappaB. FEBS Lett. 1999;442(1):89-94.

17. Randall C, Dickens A, White A, Sanders H, Fox M, Campbell J. Nettle sting for chronic knee pain: a randomised controlled pilot study. Complement Ther Med. 2008;16(2):66-72.

18. Bakhshaee M, Mohammad Pour AH, Esmaeili M, et al. Efficacy of supportive therapy of allergic rhinitis by stinging nettle (Urtica dioica) root extract: a randomized, double-blind, placebo-controlled, clinical trial. Iran J Pharm Res. 2017;16(Suppl):112-118.

19. Amiri Behzadi A, Kalalian-Moghaddam H, Ahmadi AH. Effects of Urtica dioica supplementation on blood lipids, hepatic enzymes and nitric oxide levels in type 2 diabetic patients: a double blind, randomized clinical trial. Avicenna J Phytomed. 2016;6(6):686-695.

20. Testai L, Chericoni S, Calderone V, et al. Cardiovascular effects of Urtica dioica L. (Urticaceae) roots extracts: in vitro and in vivo pharmacological studies. J Ethnopharmacol. 2002;81(1):105-109.

21. Kianbakht S, Khalighi-Sigaroodi F, Dabaghian FH. Improved glycemic control in patients with advanced type 2 diabetes mellitus taking Urtica dioica leaf extract: a randomized double-blind placebo-controlled clinical trial. Clin Lab. 2013;59(9-10):1071-1076.

22. Bnouham M, Merhfour FZ, Ziyyat A, Mekhfi H, Aziz M, Legssyer A. Antihyperglycemic activity of the aqueous extract of Urtica dioica. Fitoterapia. 2003;74(7-8):677-681.

23. Namazi N, Esfanjani AT, Heshmati J, Bahrami A. The effect of hydro alcoholic nettle (Urtica dioica) extracts on insulin sensitivity and some inflammatory indicators in patients with type 2 diabetes: a randomized double-blind control trial. Pak J Biol Sci. 2011;14(15):775-779.

24. Konrad L, Müller HH, Lenz C, Laubinger H, Aumüller G, Lichius JJ. Antiproliferative effect on human prostate cancer cells by a stinging nettle root (Urtica dioica) extract. Planta Med. 2000;66(1):44-47.

25. Fattahi S, Ardekani AM, Zabihi E, et al. Antioxidant and apoptotic effects of an aqueous extract of Urtica dioica on the MCF-7 human breast cancer cell line. Asian Pac J Cancer Prev. 2013;14(9):5317-5323.

26. Liao JC, Wei ZX, Ma ZP, Zhao C, Cai DZ. Evaluation of a root extract gel from Urtica dioica (Urticaceae) as analgesic and anti-inflammatory therapy in rheumatoid arthritis in mice. Trop J Pharm Res. 2016;15(4):781-785.

27. Nematgorgani S, Agah S, Shidfar F, Gohari M, Faghihi A. Effects of Urtica dioica leaf extract on inflammation, oxidative stress, ESR, blood cell count and quality of life in patients with inflammatory bowel disease. J Herb Med. 2017;9:32-41.

28. Hard LJ. Stinging nettles and the best ways to eat them. Food52 website. https://food52.com/blog/9935-stinging-nettles-and-the-best-ways-to-eat-them. Published March 15, 2014. Accessed August 25, 2018.