What is stinging nettle

Stinging nettle also known as Urtica dioica, is a herbaceous perennial flowering plant in the family Urticaceae, that is used in alternative medicine throughout North America and Europe to treat hay fever, asthma, diarrhea, osteoarthritis, circulation problems, diabetes, fluid retention, symptoms of enlarged prostate or benign prostatic hyperplasia (BPH), and other conditions ¹⁾. However, stinging nettle has not been proven with clinical research to be effective in treating these conditions. It is not certain whether nettle is effective in treating any medical condition. Medicinal use of this product has not been approved by the U.S. Food and Drug Administration (FDA). Stinging nettle should not be used in place of medication prescribed for you by your doctor. Stinging nettle seems to be generally well-tolerated in clinical trials and may produce mild gastrointestinal effects such as diarrhea, gastric pain, and nausea.

Stinging nettle has a long history as one among plants foraged from the wild and eaten as a vegetable ²⁾. Stinging nettle is consumed primarily as a fresh vegetable whereby it is added to soups, cooked as a pot herb, or used as a vegetable complement in dishes. In Georgia, a meal of boiled stinging nettle seasoned with walnut is common ³⁾. Romanians use sour soup made from fermented wheat bran vegetables and green nettle leaves harvested from young plants ⁴⁾. In this sense, more work needs to be done on nutritive value of fresh stinging nettle, and the fate of minerals and bioactive compounds in processed products. A comprehensive proximate analysis showed the shoots harvested from stinging nettle (Shoot) showed close to 90% moisture and rests are proteins (3.7%), fat (0.6%), ash (2.1%), dietary fiber (6.4%), total carbohydrate (7.1%), and total calories (45.7 kcal/100 g) (wet basis). Besides, Stinging nettle (shoot) contains vitamin A, vitamin C, calcium, iron, sodium, and rich fatty acid profile ⁵⁾.

Despite stinging nettle being recognized as an edible and highly nutritious vegetable, research attention has focused more on its value as a source of alternative medicine and fiber. Clinical trials have confirmed the effectiveness of stinging nettle root and saw palmetto (Serenoa repens (Bart.) Small) fruit extracts in the treatment of benign prostatic hyperplasia ⁶⁾. Dried nettle leaf preparations are also known to alleviate symptoms associated with allergic rhinitis ⁷⁾, and a technology for granulating lipophilic leaf extracts for medicine has been developed ⁸⁾. A recent report from ongoing work in Italy confirms the potential of stinging nettle as a sustainable source of textile fiber ⁹⁾.

Table 1. Stinging nettle nutrition facts

Footnotes: Approximate composition, vitamins, minerals, and fatty acid profile of raw and processed stinging nettle (Urtica dioica L.) shoots harvested from field plots in the fall of 2011 and spring of 2012.

Stinging nettle is often sold as an herbal supplement. There are no regulated manufacturing standards in place for many herbal compounds and some marketed supplements have been found to be contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Stinging nettle (Urtica dioica) is widespread through Europe and North America, and also occurs in North Africa and parts of Asia. There are naturalized populations in several other parts of the world. The stinging nettle plant has an erect stalk that grows up to 2 m in height.The soft, serrated leaves are opposite each other in pairs on the stem. The leaves and the rest of the plant are coated in stinging and non-stinging hairs. The plant spreads by underground roots which are noticeably yellow. The tiny greenish-white flowers, each with four petals, are densely clustered on elongated inflorescences towards the top of the stem. Stinging nettle (Urtica dioica) is divided into at least five subspecies, each of which is slightly different ¹¹⁾. The stinging nettle is well known for its toothed, hairy leaves and for its sting. The painful sensation of nettle stings occurs when toxins from specialized hairs are delivered into the skin. Each stinging hair has a bulbous tip which breaks off to leave a sharp, needle-like tube that pierces the skin and injects histamine and acetylcholine, causing itching and burning that may last up to 12 hours ¹²⁾.

Figure 1. Stinging nettle

Several preclinical studies demonstrating the anti-inflammatory therapeutic potential and proposed mechanism of action of stinging nettle have been reported ¹³⁾, most notably its inhibition of myeloid dendritic cells ¹⁴⁾ as well as targets in the NF-kB pathway ¹⁵⁾, however stinging nettle’s precise mechanism of action is not clear. Ten clinical trials evaluating stinging nettle use for the treatment of osteoarthritis have been conducted and generated mixed results in terms of their efficacy ¹⁶⁾, ¹⁷⁾. The root extracts of stinging nettle have also been studied clinically for treatment of benign prostatic hyperplasia (BPH) ¹⁸⁾. Also noteworthy is that the bioactive compound(s) responsible for these reported activities remains poorly understood.

A number of structural classes have been reported from extracts of stinging nettle and selected examples are shown in Figure 2 ¹⁹⁾. Surprisingly, definitive reports using bioassay guided fractionation to link any potent anti-inflammatory compound(s) derived from stinging nettle for treating osteoarthritis are lacking ²⁰⁾. In addition several different extract preparations (e.g. water, ethanol, propanol) have exhibited success clinically, making it difficult to pinpoint the overall active chemistry and further compare the efficacy of clinical studies side-by-side ²¹⁾. Traditionally water and ethanol soluble extracts of stinging nettle have been used to investigate its anti-inflammatory effects. Unfortunately, standardized stinging nettle extracts of the more polar constituents have failed to agree with clinical efficacy ²²⁾. Interestingly, few investigators have looked closely into the lipophilic extracts of stinging nettle despite previous reports of anti-inflammatory activity with potentially undefined chemistry ²³⁾.

Investigation of the stinging nettle extracts found the polar water (H2O) extracts demonstrated no ability to reduce inflammation. In fact stinging nettle water extracts of the stems and leaves demonstrated noticeable cytotoxicity in the MTT assay. Second, most of the polar stinging nettle methanol extracts including the roots, stems and leaves were far less effective than the standard anti-inflammatory agent celastrol and were comparable to a commercial ethanol extract of stinging nettle in terms of their activity ²⁴⁾. Third, in accordance with reports by others ²⁵⁾, the stinging nettle methanol extract extract of the flowering portion of nettle displayed significant anti-inflammatory activity however moderate cytotoxicity was also observed. Lastly and of particular note, the lipophilic extracts of the stinging nettle roots, stems and leaves were equivalent to or more potent than the standard endotoxin lipopolysaccharide induced inflammation in the NFkB luciferase assay and were the least cytotoxic.

Figure 2. Stinging nettle bioactive compounds

Stinging nettle uses

Stinging nettles have been used for centuries for a multitude of purposes, and continue to be harvested from the wild for food and medicine today.

Stinging nettles are eaten as a vegetable; cooking will destroy the stings. The tender, young shoots and leaves – the most palatable parts – are the main ingredient in nettle soup, which has a reputation for ‘cleansing the blood’. Historically, puddings and beer were made with stinging nettles. Today, the mature leaves are used in the production of cheese (notably Cornish Yarg) and in pesto, cordials and herbal tea. Stinging nettleshave also been used to yield vegetable protein similar to tofu made from soya ( Glycine max ). In some parts of Britain (e.g., Orkney) the leaves are traditionally fed to pigs to fatten them.

Stinging nettles have been used for a variety of medicinal purposes. A tonic prepared from the leaves is still among the most popular plant remedies used today. One traditional remedy for rheumatism involves deliberately stinging the afflicted area with nettle leaves! While this may seem strange, research has shown that nettle stings have anti-inflammatory properties that disrupt the NF-κB pathway and inhibit other inflammatory responses. Extracts of the stinging nettle root are used to treat benign prostate hyperplasia (BPH). Scientists have identified a variety of biochemical properties in extracts of nettles that support their uses in herbal medicine.

Stinging nettle stems contain tough fibers and can be used in textiles; the fiber was widely used to this effect in Germany and Austria during the First World War. Nettles can also be used for dyeing fabric. Horticulturalists sometimes use stinging nettles, which are rich in nutrients, to produce a type of liquid plant feed. The leaves are used in cosmetics.

Benign Prostatic Hyperplasia

The roots of stinging nettle have been used for urination disorders associated with benign prostate hyperplasia (BPH), as well as for joint problems, as a diuretic, and as an astringent. There is some limited evidence that stinging nettle may improve some symptoms of benign prostate hyperplasia (BPH), including lower urinary tract symptoms. There is also some limited evidence that stinging nettle and saw palmetto (Serenoa repens) may be efficacious for lower urinary tract symptoms associated with benign prostate hyperplasia (BPH).

The evidence base on efficacy of stinging nettle for benign prostate hyperplasia consists of only a few randomized controlled trials and reviews.

• A 2005 double-blind, placebo-controlled, randomized trial of stinging nettle ²⁷⁾ for treatment of benign prostate hyperplasia in 620 patients found significant improvement in International Prostate Symptom Score (IPSS), maximum urinary flow rate, and relief of lower urinary tract symptoms compared with placebo, over 6 months of treatment. These improvements were also maintained after 18 months of treatment.
• Other studies have examined the effects of a combination of Serenoa repens and stinging nettle. A 2007 randomized controlled trial in 257 patients with moderate and severe symptoms of benign prostate hyperplasia ²⁸⁾ found that the combination treatment over the course of 6 months was superior to placebo for attenuation of inflammatory and obstructive symptoms. Another study in Germany ²⁹⁾ compared the effects of the same combination to tamsulosin in 140 men for 15 months and found both treatments to be efficacious for lower urinary tract symptoms caused by benign prostate hyperplasia.

Stinging nettle contraindications

Due to the effects on androgen and estrogen metabolism, stinging nettle preparations are contraindicated in pregnancy and lactation and should not be used in children younger than 12 years.

Stinging nettle dosage

Freeze-dried stinging nettle leaf 600 mg has been used in a clinical trial for allergic rhinitis. Clinical trials for benign prostatic hyperplasia (BPH) have used aqueous stinging nettle root extracts 360 mg daily over 6 months and methanol root extract 600 to 1,200 mg daily for 6 to 9 weeks.

Stinging nettle allergies

Stinging nettles are known primarily for their ability to induce topical irritation following contact with exposed skin. The painful sensation of nettle stings occurs when toxins from specialized hairs of the stinging nettle leaves and stem are delivered into the skin. Each stinging hair has a bulbous tip which breaks off to leave a sharp, needle-like tube that pierces the skin and injects histamine and acetylcholine, causing acute urticaria, itching and burning that generally resolves spontaneously within 12 hours ³⁰⁾.

A 17-day-old exclusively breastfed infant was admitted to the hospital with an urticarial rash on the chest, back, and upper extremities ³¹⁾. The infant’s mother had reportedly applied water boiled with stinging nettles for cracked nipple twice a day before and after each breastfeeding for 2 days. Total IgE and specific IgE levels for stinging nettle were high in the mother and infant. The infant’s rash improved upon cessation of breastfeeding. Breastfeeding was resumed 2 days later without the use of stinging nettle on the nipple and the rash did not recur. At 2 months of age, skin prick testing in the infant was positive for stinging nettle, but no other allergen tested positive. Stinging nettle exposure was the probable cause of the rash ³²⁾.

Stinging nettle side effects

Although not all side effects are known, stinging nettle is thought to be possibly safe when taken for a short period of time (no longer than 6 months).

Common side effects of stinging nettle supplement or extract may include:

• sweating;
• skin irritation; or
• stomach discomfort including diarrhea, gastric pain, and nausea.

Case reports of hypoglycemia ³³⁾ due to consumption of nettle preparations for prostatic hypertrophy exist, as well as gynaecomastia and galactorrhea ³⁴⁾. Due to the effects on androgen and estrogen metabolism, stinging nettle preparations are contraindicated in pregnancy and lactation and should not be used in children younger than 12 ³⁵⁾.

Single cases of gynecomastia in a man and galactorrhea in a woman were reported after ingesting stinging nettle as a tea for 4 weeks prior to seeking medical advice ³⁶⁾. Serum hormones were normal in the man, but serum estradiol was very high, prolactin was slightly elevated, and LH and FSH were low in the woman. Both conditions reversed 4 to 6 weeks after stopping the tea. The case reports were from Turkey where ingestion of nettle is common. No analysis of the tea was performed to test for foreign substances. The relevance of these findings with respect to breastfeeding are not known. The prolactin level in a mother with established lactation may not affect her ability to breastfeed.

A randomized trial assigned mothers of preterm infants to receive either a purported herbal galactogogue tea twice daily, a fruit tea twice daily or nothing. The galactogogue tea contained stinging nettle, lemon balm, caraway, anise, fennel, goat’s rue, and lemon grass ³⁷⁾. All received similar breastfeeding advice from the same nurse and two groups were told that the tea would increase milk production, but compliance with the study teas was not assessed. The study was not blinded, and not analyzed on an intent-to-treat basis. Mother used breast pumps to extract and measure their milk output on day 1 and day 7 of the study. Although the volume of extracted milk was greater in the galactogogue tea group, there was no difference in infant weight gain nor in maternal serum prolactin between the groups at 7 days ³⁸⁾.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficult breathing; swelling of your face, lips, tongue, or throat.

What other drugs will affect stinging nettle?

Taking stinging nettle with any medicines that make you sleepy can worsen this effect. Ask your doctor before taking stinging nettle with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Do not take stinging nettle without medical advice if you are using any of the following medications:

• lithium;
• blood pressure medication;
• insulin or oral diabetes medicine; or
• warfarin (Coumadin, Jantoven).

A 2015 review ³⁹⁾ noted that stinging nettle contains tannins, which can interact with a concomitant intake of iron, causing a reduction of the effects in patients who need iron supplements.

This list is not complete. Other drugs may interact with stinging nettle, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed here.

Toxicology

The acute oral LD 50 (lethal dose 50 is the dose where 50% of the test subjects die) in rats has been estimated to be greater than 30 g/kg for the aqueous stinging nettle leaf extract and 1.3 g/kg for the stinging nettle root ⁴⁰⁾, ⁴¹⁾. Liver function tests in rats fed aqueous nettle extracts for 30 days were normal ⁴²⁾. Older mutagenicity and carcinogenicity studies have been negative for the aqueous stinging nettle extract ⁴³⁾.

What is colostrum

Colostrum is also called liquid gold for its deep yellow color, colostrum is the thick first milk that women make during pregnancy and just after birth. Colostrum milk is very rich in nutrients, fluid and includes antibodies to protect your baby from infections in the early days. Colostrum color and thickness are due to the fact that it is higher in these protective factors. Compared with more mature human milk, colostrum is also higher in protein, slightly lower in sugar, and significantly lower in fat. Colostrum also helps your newborn infant’s digestive system to grow and function. Your baby gets only a small amount of colostrum at each feeding because the stomach of a newborn infant is tiny and can hold only a small amount.

Colostrum changes into mature milk by the third to fifth day after birth. This mature milk has just the right amount of fat, sugar, water, and protein to help your
baby continue to grow. It looks thinner than colostrum, but it has the nutrients and antibodies your baby needs for healthy growth.

Research suggests that breastfed babies have lower risks of ¹⁾:

•  Asthma
• Childhood leukemia
• Childhood obesity
• Ear infections
• Eczema (atopic dermatitis)
• Diarrhea and vomiting
• Lower respiratory infections
• Necrotizing enterocolitis, a disease that affects the gastrointestinal tract in preterm infants
• Sudden infant death syndrome (SIDS)
• Type 2 diabetes

Breastfed babies may also be sick less often, which can help keep your baby’s health costs lower.

Breastfeeding is good for the mother’s health too. Breastfeeding is linked to a lower risk of Type 2 diabetes, certain types of breast cancer, and ovarian cancer in mothers ²⁾.

Table 1. Composition of human and bovine colostrum

Colostrum supplement

Bovine colostrum has been used in therapeutic medicine for years by many cultures around the world ⁴⁾. Bovine colostrum supplements are sold in the form of powder and tablets. Just like human colostrum, bovine colostrum is a milk secreted by cows during the first few days after calving, and its importance for the health of calves has been known for a long time ⁵⁾. Colostrum contains not only nutrients like proteins, carbohydrates, fat, vitamins, and minerals but also bioactive components like growth factors and antimicrobial factors ⁶⁾. Colostrum contains immunoglobulins, lactoferrin, proline-rich polypeptide, cytokines, vitamins, minerals and growth factors, and is characterized by higher protein content than regular milk. However, the content of the different food constituents in bovine colostrum is not well-defined and varies among products available on the market. Bovine colostrum is a protein-rich cocktail that contains several nutritional and immunological factors that provide a strong nutritional base for the newborn animal ⁷⁾. Growth factors in colostrum include insulin‐like growth factors and transforming growth factors and are believed to play an important role in the development of skeletal muscle ⁸⁾, gastrointestinal differentiation ⁹⁾ and cell repair ¹⁰⁾. The importance of colostrum for human neonate immune system development is well recognized ¹¹⁾ and the presence of closely homologous bioactive components in bovine colostrum has led to the growing use of bovine colostrum in humans.

The results of the study done by Appukutty et al. ¹²⁾ showed that there was a main effect of time and significant impact on antioxidant levels including, lipid peroxidation, superoxide dismutases, xanthine oxidase and total antioxidant, all of which indicate a positive influence following colostrum supplementation. There are studies reporting that antioxidants are incapable of extending exercise-induced lifespan extension in rats ¹³⁾. Exercise-induced reactive oxygen species itself are known to increase endogenous reactive oxygen species defense capacity in skeletal muscles ¹⁴⁾ and antioxidant supply may prevent the induction of molecular regulators of endogenous antioxidant defense in the skeletal muscles during exercise. But the results of this study showed that the exercise group had increased levels of oxidative stress. Moderate levels of reactive oxygen species in any tissue are necessary for the normal homeostatic process but excessive production causes oxidative stress. With increased intensity and prolonged exercise, a skeletal muscle mitohormesis process might have been suppressed to cause increased oxidative stress. Accumulated reactive oxygen species during prolonged exercise might have enhanced oxidative damage in skeletal muscles as the muscle proteins are highly redox sensitive ¹⁵⁾. Chiang and Chang ¹⁶⁾ reported antioxidant properties of caseins and whey proteins in colostrum. Colostrum contains significantly higher quantities of antioxidants which is very crucial for health to protect against oxidative stress in infants. It is known that at birth, the newborns will go through many challenges and one such challenge is adaptation to the oxygen-rich environment compared to the low-oxygen intrauterine environment ¹⁷⁾. However, this situation may be overcome by the generation of excessive reactive oxygen species [ROS]. Few studies have shown that higher concentrations of antioxidants instead of protecting skeletal muscles against oxidative stress, increases oxidative damage during exercise. Higher concentrations of antioxidants are reported to eliminate the reactive oxygen species which normally play an important role in the regulation of redox sensitive muscle proteins during muscle contractions ¹⁸⁾. But the results of this study ¹⁹⁾ demonstrated that concurrent colostrum treatment was able to improve the total antioxidant levels and increase the skeletal muscle superoxide dismutase level and reduce the lipid hydroperoxide and xanthine oxidase formation. These results demonstrated that bovine colostrum may have a significant antioxidant effect in skeletal muscle after muscular exercise.

Bovine colostrum is currently promoted as a supplement in sports nutrition for muscle recovery, anaerobic sports functions and also to some extent for its anti-aging property ²⁰⁾. Limited research to date suggests that bovine colostrum supplementation enhances exercise performance and recovery ²¹⁾. Bovine colostrum supplementation at 60 g/day for 8 weeks has been shown to improve repeat sprint performance in elite hockey players ²²⁾, peak vertical jump power and peak cycle power ²³⁾ and peak running speed during a repeated bout of intense exercise ²⁴⁾. In addition, a 20 g/day dose and a 60 g/day dose over 8 weeks have both been reported to improve cycle time trial performance ²⁵⁾. Whether a smaller and hence more economical dose can enhance exercise performance is yet to be established.

On the contrary, other research could not prove positive effects supplementing with bovine colostrum on strength or speed performances ²⁶⁾. One of the earliest studies that investigated the effect of bovine colostrum supplementation on sporting performance in humans showed that eight days of low-dose bovine colostrum supplementation during speed and strength training did not have any effect on vertical jump or recovery from exercise ²⁷⁾. However, later studies have shown that eight-weeks of bovine colostrum supplementation of 20 g per day during endurance and resistance training significantly increased lean body mass, but no effect was observed on bench press performance ²⁸⁾; while daily supplementation of 60 g bovine colostrum per day for eight-weeks significantly improved sprint ability and indicated a trend towards improved vertical jump test performance ²⁹⁾.

Several studies have reported the use of bovine colostrum for immune responses and sporting performance with doses ranging from 20 to 60 g per day ³⁰⁾. Bovine colostrum supplementation at 60 g/day enhances repeat running and cycling performance during normal training periods and the recent study has reported a dose as low as 10 g per day that have proven to have a significant effect on human cycling performance during high intensity training ³¹⁾. Improvements in performance study were observed in a 12-minute cycloergometer test after ingesting 20 g/day of bovine colostrum compared to 60 g/day ³²⁾, and thus, it is feasible to suggest supplementing with 20 g/day of bovine colostrum, with the goal being to improve the immune function, and possibly improving performance.

In another study on the effect of bovine colostrum supplementation in older adults during resistance training ³³⁾, showed colostrum supplementation during resistance training was beneficial for increasing leg press strength and reducing bone resorption in older adults. Both colostrum and whey protein groups improved upper body strength, muscle thickness, lean tissue mass, and cognitive function.

Colostrum health benefits

The European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies ³⁴⁾ was asked to provide a scientific opinion on a list of health claims related to bovine colostrum in relation to the following claimed effects: “immune health/source of immunoglobulins”, “supports immune function during periods of intense physical exercise”, “supports an improvement in exercise performance when combined with regular training”, “supports an increase in lean body mass when combined with resistance exercise”, “supports recovery following intense exercise”, “digestion health: bovine colostrum might help for the treatment of colitis/prevents diarrhoea, diminishes colicky symptoms/bovine colostrum is effective in the management of gastrointestinal disorders”, and “anti-asthénique (récupération)”. The European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies considers that the food constituent, bovine colostrum, which is the subject of this opinion, is not sufficiently characterized in relation to the claimed effects considered in this opinion. The Panel concludes that a cause and effect relationship cannot be established between the consumption of bovine colostrum and the claimed effects considered in this opinion ³⁵⁾.

The European Food Safety Authority Panel notes that the references provided for the substantiation of the health claims considered in this opinion have used as intervention either concentrated bovine colostrum protein (i.e. standardised, low heat, low fat, low lactose colostrum powder containing 20 % Immunoglobulin G (IgG) by weight) which includes both casein and whey proteins, ³⁶⁾, ³⁷⁾, ³⁸⁾, whole bovine colostrum in powder form for which only energy and macronutrient composition was provided ³⁹⁾, or immunoglobulin-enriched bovine colostrum ⁴⁰⁾, and that the characterization of the food, which is the subject of the health claims, is unclear. The Panel also notes that the concentrations of various components of bovine colostrum which are proposed to contribute to the claimed effects (e.g. lactoferrin, immunoglobulins, epidermal growth factor, transforming growth factor, etc.) have not been provided.

The European Food Safety Authority Panel ⁴¹⁾ considers that the food constituent, bovine colostrum, which is the subject of this opinion, is not sufficiently characterized in relation to the claimed effects.

The European Food Safety Authority Panel ⁴²⁾ concludes that a cause and effect relationship cannot be established between the consumption of bovine colostrum and the claimed effects.

CONCLUSIONS

On the basis of the data presented, the European Food Safety Authority Panel ⁴³⁾ concludes that:

The food constituent, bovine colostrum, is not sufficiently characterized in relation to the claimed effects considered in this opinion. A cause and effect relationship cannot be established between the consumption of bovine colostrum and the claimed effects considered in this opinion.

Colostrum side effects

Studies of human volunteers in the various intervention trials have shown no inducement of antibodies and no intact uptake of bovine immunoglobulins ⁴⁴⁾. All of this is supported by the cultural evidence of traditional consumption of colostrum in diverse pastoralist groups around the world. Milk-allergic individuals can be expected to have allergic potential with bovine colostrum. Indeed, a recent serological study of milk-allergic patients found IgE cross-reactivity with colostral IgG ⁴⁵⁾.

What is soy lecithin

Soy lecithin is a by-product from the processing of soybean oil. Soy lecithin is widely used in the food industry as an emulsifier and stabilizing agent in the production of foods such as margarine, mayonnaise, chocolate and baked goods ¹⁾. Lecithin is the common name for a series of related compounds called phosphatidylcholines. Lecithins are mixtures or fractions of phosphatides obtained by physical procedures from animal or vegetable foodstuffs found mainly in egg yolks, soy (soybeans), organ and lean meats, fish and coleseeds. The total phospholipids contained in 100 g of egg yolk and soybeans are 31.8 g and 20.8 g, respectively ²⁾, and the normal dietary intake of phospholipids is estimated as 2–8 g per day ³⁾. Crude lecithin is a mixture of mainly phospholipids (up to approximately 75 % for de-oiled lecithin), i.e., phosphatidylcholine, phosphatidylethanolamine and phosphatidylinositol and a smaller fraction of glycolipids, neutral lipids, and carbohydrates, that can be extracted from plant or animal food substances ⁴⁾. Dietary crude lecithin is a source of active compounds as it is digested into fatty acids, lysophospholipids, phosphatidic acid, glycerol, monoglycerides, and other compounds, including choline and ethanolamine. Lecithin has low solubility in water, but is a very good emulsifier and is also a source of active compounds, such as choline, that can be released from phosphatidylcholine. Lecithin is a choline-containing phospholipid and is the major dietary source of choline. It has been shown to increase serum choline levels more effectively than orally administered choline ⁵⁾. Wurtman et al. ⁶⁾ found that oral lecithin is considerably more effective in raising human serum-choline levels than an equivalent quantity of choline chloride. 30 minutes after ingestion of choline chloride (2·3 g free base), serum-choline levels rose by 86% and returned to normal values within 4 hours; 1 hour after lecithin ingestion, these levels rose by 265% and remained significantly raised for 12 hours. Lecithin may therefore be the method of choice for accelerating acetylcholine synthesis by increasing the availability of choline, its precursor in the blood.

There are three forms of lecithins (i) regular liquid lecithins, derived from soybean, rapeseed and sunflower; (ii) hydrolysed liquid lecithins, derived from soybean and sunflower; (iii) de‐oiled lecithins powder derived from soybean and sunflower.

Soy lecithin allergy

Soybean allergy is one of the most common food allergies especially among children. Approximately 0.4% of children are allergic to soy but about half of them spontaneously recover by the age of 7 years ⁷⁾. Allergic reactions to soy lecithin have been previously reported in the literature: occupational asthma in bakers ⁸⁾, chronic diarrhea in a child ⁹⁾, and anaphylactic reaction in a 40-year-old woman treated with an inhalatory drug ¹⁰⁾. In general, soy allergy is not as common as cow’s milk allergy, even in atopic children. Bruno et al. ¹¹⁾ found a prevalence of 1.2% in a cohort of 505 children suffering from allergic diseases and 0.4% in 243 children who had been fed soy protein formula in the first 6 months of life for supposed prevention of allergic diseases. Patients with soy allergy show a wide range of immunoglobulin E (IgE) and non IgE-mediated clinical symptoms ¹²⁾. For these reasons, the Food Allergen Labeling and Consumer Protection Act in the US, from January 1, 2006, mandates labeling of all ingredients derived from commonly allergenic foods, including soybeans, with the exception of highly refined oils ¹³⁾. The Food Allergen Labeling and Consumer Protection Act also requires the labeling of soy lecithin because it is derived from soybeans and may contain a number of IgE-binding proteins, possibly representing a source of hidden allergens ¹⁴⁾. Soy lecithin is not only used in the food industry, as an antioxidant, but it is widely used in topical skin care products, in various drugs administered either topically, orally, intravenously or by inhalation, as an emulsifier ¹⁵⁾.

In 2014, the European Food Safety Authority Panel on Dietetic Products, Nutrition and Allergies ¹⁶⁾ prepared a scientific opinion on the evaluation of allergenic foods and food ingredients for labeling purposes where the allergenicity of egg and soya lecithins were considered. The possibility of residual allergenicity in food products manufactured using egg lecithin has been reported in a double‐blind placebo‐controlled food challenge. Heat denaturation and other food‐processing treatments do not reliably reduce the allergenicity of egg. Minimum eliciting doses (MEDs) of ingested egg proteins reported to trigger objective reactions in clinical studies range from few micrograms to milligrams.

The prevalence of clinically confirmed soya allergy in unselected populations in Europe appears to be low, although available studies are scarce. The sodium dodecyl sulfate polyacrylamide gel electrophoresis protein pattern of the standard soya lecithin is very similar to that of soya flour. The lowest minimum eliciting dose reported in soya‐allergic patients undergoing double‐blind placebo‐controlled food challenge was 0.2 mg of soya protein, although the majority of patients only reacted to higher doses ¹⁷⁾.

Soybeans and eggs and products thereof (including lecithins) are listed as substances or products causing allergies or intolerances which indication as allergens is mandatory food information.

Table 1. Presentation of soy allergy (and cow’s milk allergy)

Allergic reactions to soy are typically mild, but all reactions can be unpredictable. Although rare, severe and potentially life-threatening reactions can also occur. If you have a soy allergy, keep an epinephrine auto-injector (such as an EpiPen®, Auvi-Q™ or Adrenaclick®) with you at all times. Epinephrine is the first-line treatment for anaphylaxis.

Avoiding Soy

The close resemblance and resultant cross-reactivity between proteins from soy and other related plants like peanut, and the lack of predictive values for clinical reactivity, often make the diagnosis of soy allergy far more challenging. Furthermore, diagnostic tests for non-IgE-mediated manifestations are lacking. Avoidance of the culprit food protein is the mainstay of therapy, although there is a growing body of evidence on the efficacy of investigational new therapies such as oral or sublingual immunotherapy.

To prevent a reaction, it is very important that you avoid soy and soy products. Always read food labels and ask questions about ingredients before eating a food that you have not prepared yourself.

Soybeans alone are not a common food in American diets. Instead, they are widely used in processed food products. Eliminating all those foods can result in an unbalanced diet. A dietitian can help you plan for proper nutrition.

Soy is one of the eight major allergens that must be listed on packaged foods sold in the U.S., as required by federal law.

Avoid foods that contain soy or any of these ingredients:

• Cold-pressed, expelled or extruded soy oil*
• Edamame
• Miso
• Natto
• Shoyu
• Soy (soy albumin, soy cheese, soy fiber, soy flour, soy grits, soy ice cream, soy milk, soy nuts, soy sprouts, soy yogurt)
• Soya
• Soybean (curd, granules)
• Soy protein (concentrate, hydrolyzed, isolate)
• Soy sauce
• Tamari
• Tempeh
• Textured vegetable protein
• Tofu

*Highly refined soy oil is not required to be labeled as an allergen. Studies show that most people with soy allergy can safely eat highly refined soy oil as well as soy lecithin. If you are allergic to soy, ask your doctor whether you need to avoid soy oil or soy lecithin.

But avoid cold-pressed, expelled or extruded soy oil—sometimes called gourmet oils. These ingredients are different and are not safe to eat if you have a soy allergy.

Soy is sometimes found in the following:

• Asian cuisine (including Chinese, Indian, Indonesian, Thai and Vietnamese)—even if you order a soy-free item, there is high risk of cross-contact
• Vegetable gum
• Vegetable starch
• Vegetable broth

Cross-contact occurs when an allergen is inadvertently transferred from a food containing an allergen to a food that does not contain the allergen. Cooking does not reduce or eliminate the chances of a person with a food allergy having a reaction to the food eaten.

Examples of cross-contact and how to avoid it:

Say a knife that has been used to spread peanut butter is only wiped off before being used to spread jelly. There could be enough peanut protein remaining on the knife to cause a reaction in a person who has a peanut allergy. All equipment and utensils must be cleaned with hot, soapy water before being used to prepare allergen-free food.

Even a trace of food on a spoon or spatula that is invisible to you can cause an allergic reaction.

Some Unexpected Sources of Soybeans and Soy Products:

• Baked goods
• Canned broths and soups
• Canned tuna and meat
• Cereals
• Cookies
• Crackers
• High-protein energy bars and snacks
• Infant formulas
• Low-fat peanut butter
• Pet food
• Processed meats
• Sauces
• Soaps and moisturizers

Allergens are not always present in these foods and products, but soy can appear in surprising places. Again, read food labels and ask questions if you’re ever unsure about an item’s ingredients.

Figure 1. Tips for Avoiding Food Allergens

[Source ¹⁹⁾

Will children outgrow a soy allergy?

About 0.4 percent of children are allergic to soy. Studies show an allergy to soy usually occurs early in childhood and often is outgrown by age three. The majority of children with soy allergy will outgrow the allergy by age 10 ²⁰⁾.

With soy allergy, most people become tolerant over time, although as with cow’s milk allergy, it may take longer than previously thought. Savage et al. ²¹⁾ retrospectively described the natural history of 133 patients allergic to soy (88% with concomitant peanut allergy) with a variety of clinical reactions and found that approximately 50% of the children outgrew their allergy by age 7 years and 69% by 10 years. By age 6 years, peak soy-specific IgE level less than 10 kUA/L was predictive of >50% chance of outgrowing allergy, but peak level more than 50 kUA/L suggested <20% chance of tolerance development. Although soy allergy is commonly considered to have an early onset, the study identified a subset of patients with late onset soy allergy whose symptoms started after tolerating soy on a regular basis in their diet. Savage et al. ²²⁾ suggested that such late-onset soy allergy may be related to either birch pollen cross-reactivity or persistent peanut allergy, as indicated by a very high peanut-specific IgE levels at their last follow-up. Notably, the prevalence of soy sensitization progressively increased with age from 2% at age 2 years to 7% at 10 years in the German Multi-Center Allergy Study, which followed 1314 children from birth to age 13 ²³⁾.

Food protein-induced enterocolitis responds well to dietary elimination of the offending food, with tolerance usually developing within 3 years of life ²⁴⁾, although rate of tolerance development varies between studies and populations. Occasionally food protein-induced enterocolitis may persist into the teenage years. Earlier reports suggested that within 2 years, 60% of milk and 20% of soy-induced food protein-induced enterocolitis resolves ²⁵⁾. Preliminary data on 76 subjects with food protein-induced enterocolitis shows that the majority of patients with milk food protein-induced enterocolitis become tolerant by 3 to 4 years, but the natural history was not as favorable for soy ²⁶⁾. However, a recent study by Korean investigators on 23 infants with milk food protein-induced enterocolitis reported that 64% tolerated milk at 10 months, and 92% tolerated soy at 10 months ²⁷⁾.

What is food protein-induced enterocolitis?

Food protein-induced enterocolitis is when dietary protein-induced syndromes of enteropathy and enterocolitis are not IgE-mediated, and typically present with profuse vomiting and diarrhea within 2–3 hours after ingestion of the offending allergen, causing profound dehydration and lethargy ²⁸⁾. Three quarters of infants with FPIES appear acutely ill, and about 15% have hypotension requiring hospitalization ²⁹⁾. Mehr et al. ³⁰⁾ reported that one quarter of acute food protein-induced enterocolitis syndrome episodes in young infants manifested with hypothermia less than 36°C. The diarrhea may have occult blood, and fecal smears reveal leukocytes and eosinophils. Chronic exposure to the offending allergen results in a less acute clinical presentation of failure to thrive and hypoalbuminemia ³¹⁾. Sicherer et al reported that food protein-induced enterocolitis syndrome was elicited most often by cow milk and soy protein, with 7 of 16 patients having sensitivity to both ³²⁾. Similarly, Burks et al. ³³⁾ reported that 6 of 10 patients with food protein-induced enterocolitis syndrome reacted to both milk and soy. Preliminary data on 76 patients with food protein-induced enterocolitis syndrome showed cow milk was the trigger in 58% and soy in 47% of patients ³⁴⁾. Among children with milk-food protein-induced enterocolitis syndrome, 45% had soy-food protein-induced enterocolitis syndrome and among children with soy-food protein-induced enterocolitis syndrome, 56% had milk-food protein-induced enterocolitis syndrome.

Protein-induced allergic enterocolitis/proctitis/proctocolitis usually presents by 6 months of life in an otherwise well-appearing breastfed or formula-fed infant with blood-streaked, mucousy, loose stools and occasionally diarrhea ³⁵⁾. Cow milk and soy are the major causative foods. The majority of breastfed infants with allergic proctocolitis respond to maternal elimination of cow milk proteins, although some require the additional elimination of soy ³⁶⁾ or conversion to extensively hydrolyzed formula. Other causes, such as viruses, may have a similar presentation ³⁷⁾. Despite concerns regarding co-sensitization or allergy to soy in cow milk allergic subjects, soy-based formulas continue to be a management option for cow’s milk allergic infants with IgE-mediated reactions, especially above 6 months of age.

Lecithin in food

Lecithin is found in many animal and vegetable sources including beef liver, steak, eggs, peanuts, cauliflower, and oranges ³⁸⁾. Commercial sources for lecithin can come from soybeans, egg yolk, or brain tissue ³⁹⁾. Some commercial lecithin and lecithin supplements contain between 10% and 35% phosphatidylcholine ⁴⁰⁾.

Is soy lecithin bad for you?

According to the 2017 re-evaluation of lecithins as a food additive by the European Food Safety Authority ⁴¹⁾, the European Food Safety Authority Panel concluded that there was no need for a numerical acceptable daily intake (ADI) for lecithins (E 322) and that there was no safety concern for the general population from more than 1 year of age at the refined exposure assessment for the reported uses of lecithins (E 322) as a food additive. The European Food Safety Authority Panel further concluded that there is no safety concern for the exposure to the choline from lecithins (E 322) as a food additive at use and use levels reported by industry ⁴²⁾. For infants (from 12 weeks up to 11 months of age), the European Food Safety Authority Panel concluded that there was no safety concern at the refined exposure assessment for the reported uses of lecithins (E 322) as a food additive and for the choline from lecithins (E 322) as a food additive at use and use levels reported by industry ⁴³⁾. For infants and young children consuming foods for special medical purposes, the European Food Safety Authority Panel concluded that there was no safety concern with respect to the refined exposure assessment for the reported uses of lecithins (E 322) as a food additive and for exposure to choline resulting from these uses of lecithins (E 322) ⁴⁴⁾. The present opinion deals with the re‐evaluation of lecithins (E 322) when used as a food additive and does not include lecithin supplement.

Lecithins (E 322) is an authorized food additive as emulsifying agents in the European Union ⁴⁵⁾ and in the U.S. Food and Drug Administration (FDA) has determined lecithin to be generally recognized as safe (GRAS) for addition to food ⁴⁶⁾. Lecithin has been widely used in foods (e.g., infant formula and chocolate) as a natural emulsifier to improve physical stability ⁴⁷⁾. In humans, dietary lecithins are hydrolysed by phospholipases to liberate choline which is rapidly absorbed and appears in plasma predominantly as free choline. The European Food Safety Authority Panel considered that dietary intakes of lecithins (E 322) from the regular diet could be estimated in average ranging from 4 to 71 mg/kg body weight per day across all population age groups ⁴⁸⁾.

The European Food Safety Authority Panel concluded that there was no need for a numerical acceptable daily intake (ADI) for lecithins (E 322) and that there was no safety concern for the general population from more than 1 year of age at the refined exposure assessment for the reported uses of lecithins (E 322) as a food additive.

Taking into consideration that:

• hydrolysed lecithins and choline are produced in the gut as a result of normal digestion of lecithins. Choline is rapidly absorbed and appears in plasma predominantly as free choline,
• choline is a precursor of the neurotransmitter acetylcholine,
• the content of choline, that can theoretically be released from phosphatidylcholine containing two linoleate groups, is up to 13.2%, and the measured content of choline from commercial lecithins (E 322) up to 3.4%,
• 13.2% release would result in exposure up to 23 mg choline/kg bw per day at the 95th percentile intake of lecithins in toddlers (brand loyal scenario),
  total choline intake considering regular diet (estimated in average ranging from 4 to 18 mg/kg bw per day) across all population age groups and choline intake resulting from lecithins (E 322) used as a food additive are below the upper intake level (UL) for choline defined by the Institute of Medicine ⁴⁹⁾,

The European Food Safety Authority Panel concluded that there is no safety concern for the exposure to the choline from lecithins (E 322) as a food additive at use and use levels reported by industry ⁵⁰⁾.

However, the European Food Safety Authority Panel noted that, the use levels of lecithins (E 322) in food for infants under the age of 12 weeks and because these uses would require a specific risk assessment; therefore, the existing evaluation of lecithins (E 322) as a food additive is not considered to be applicable for infants under the age of 12 weeks ⁵¹⁾. The European Food Safety Authority Panel noted that it is prudent to keep the number of additives used in foods for infants and young children to the minimum necessary.

The acute toxicity of lecithins (E 322) in mice, rats and rabbits is low. Subchronic toxicity studies in rats and dogs did not report any adverse effect, even at the highest doses tested (3,750 mg essential phospholipid/kg body weight per day, 1,000 mg soya phosphatidylinositol or essential phospholipid/kg body weight per day in rats and dogs, respectively, and 5,460 mg lecithins/kg body weight per day in rats). The European Food Safety Authority Panel considered the available genotoxicity data on lecithins (E 322) to be sufficient to conclude that there is no concern with respect to genotoxicity ⁵²⁾. Chronic toxicity studies in rats did not report any adverse effects, even at the highest dose tested (3,750 mg essential phospholipid/kg body weight per day). No carcinogenic effects were reported in rats, even at the highest dose tested (1,470 and 2,280 mg soya lecithin/kg body weight per day in males and females, respectively) for 2 years ⁵³⁾. Several neurodevelopmental toxicity studies were conducted with lecithin. The European Food Safety Authority Panel concluded that the relevance of the studies is limited but, at concentrations of 5% soya lecithin and higher in the diet during the gestation, lactation and the post‐weaning period, there were indications for alterations in the development of the brain ⁵⁴⁾.

What is lecithin good for?

Soy lecithin is widely used in the food industry as an emulsifier and stabilizing agent in the production of foods such as margarine, mayonnaise, chocolate and baked goods. Lecithin is also used as an emulsifying and stabilizing agent in pharmaceutical, and cosmetic (eg, creams, lipsticks, conditioners) industries. Lecithin is also consumed because of its purported health benefits. A review ⁵⁵⁾ reported numerous data supporting the effect of lecithin in lowering the blood cholesterol level in hyperlipidemic animals and humans.

Lecithin is also sold as an herbal supplement. There are no regulated manufacturing standards in place for many herbal compounds and some marketed supplements have been found to be contaminated with toxic metals or other drugs. Herbal/health supplements should be purchased from a reliable source to minimize the risk of contamination.

Lecithin has been used in alternative medicine as a possibly effective aid in treating liver disease.

Lecithin has also been used to treat gallbladder disease, dementia related to Alzheimer’s disease, age related loss of memory, and head injuries. However, research has shown that lecithin may not be effective in treating these conditions.

Other uses not proven with clinical research have included high cholesterol, manic-depressive disorder, dermatitis, improvement of athletic performance, Parkinson’s disease, stress, insomnia, and other conditions.

It is not certain whether lecithin is effective in treating any medical condition. Medicinal use of this product has not been approved by the FDA. Lecithin should not be used in place of medication prescribed for you by your doctor.

Soy lecithin on cholesterol

Lecithin is one of the nature elements that have dispersing properties. That is why it can emulsify fat, avoiding its absorption. Lecithin is capable of reducing LDL “bad” cholesterol. It also promotes the HDL “good” cholesterol synthesis ⁵⁶⁾. In addition to be used to help reduce cholesterol and triglycerides and protect the liver in the prevention of kidney stone formation, it is used as a tonic for the nervous system and brain activities. The Food and Drug Administration-(FDA) USA, and the World Federation of Cardiology recommended the use of 25 grams per day of soy protein, which corresponds to approximately 60 g of soybeans for cardiovascular disease prevention. However, it is not yet clear which components of soy are responsible for their antiatherogenic purposes.

Recent studies suggest that a lecithin-rich diet can modify the cholesterol homeostasis and lipoprotein metabolism in liver. Lecithin diet modifies the cholesterol homeostasis in the liver, increasing the HMG-CoA reductase and alpha 7 hydroxylase cholesterol activities and decreasing the microsomal ACAT activity. The LDL concentration and size are also significantly reduced and the bile acid pool and bile lipid secretion are increased ⁵⁷⁾.

In this study ⁵⁸⁾, soy lecithin effect on the serum cholesterol concentration involving thirty volunteers (58–70 years old) was evaluated with one soy lecithin capsule 500 mg [22% phospholipid (phosphatidiletanolamine), 10% triacylglycerol, and 68% phosphatidylcholine] administrated daily for 2 months. The results showed a decrease of 40.65% and 42.60% in total cholesterol and 42.65% and 56.11% in LDL “bad” cholesterol, one and two months after administration, respectively. However, further works with a large number of patients should be carried out towards finding the ideal dose-response.

Lecithin-rich diets can stimulate the fatty acid secretion with high levels of cholesterol and phospholipids when compared with diets without lecithin, considering the lecithin performance as phytotherapic, with a large spectrum of activity. The results showed significant reduction in the concentration of total cholesterol and LDL-cholesterol during the first month, suggesting that the daily administration of lecithin capsule could be used as an adjuvant treatment in hypercholesterolemia, possibly by reducing the intestinal absorption or by the increased secretion of bile acids with high levels of cholesterol and phospholipids ⁵⁹⁾.

Soybean presents a number of advantages compared with other sources of vegetable protein ⁶⁰⁾. It has high-protein content (38%–42%) of low cost and high quality as well as isoflavones that help in reducing blood cholesterol. The daily intake of 25 grams of soy protein dramatically reduced the total cholesterol over a period of approximately three weeks, that is, one month after treatment beginning. It was also shown that this effect was not dependent on time, since there was no increase two months after the treatment end. The daily intake of soy protein may reduce the LDL concentration by 30%, while occurs a stimulus for the HDL “good” cholesterol production ⁶¹⁾.

Soybean protein increases the cholesterol-lowering effects of plant sterols on rats fed cholesterol; the combination of plant sterols and soy protein increases fecal neutral sterols and bile acid excretion compared with the sterol and soy protein alone; therefore, the combination of sterol and soy protein shows a more ostensible decrease in plasma lipids than the isolated ingredients ⁶²⁾.

A decrease in the cholesterol intestinal absorption and an increase in the bile acid excretion have been suggested as possible mechanisms for the effects in the reduction of lipids by soy protein ⁶³⁾.

Jiang et al. ⁶⁴⁾ demonstrated the inhibition of cholesterol absorption in diets rich in phosphatidylcholine. This study suggests that the high degree of saturation of acyl groups of the soybean phosphatidylcholine decreases the cholesterol intestinal absorption.

Neurologic disorders

Lecithin is a good source of choline for treatment in dementias ⁶⁵⁾. Phosphatidylcholine is thought to be a precursor for acetylcholine (Ach) synthesis ⁶⁶⁾. Choline increases the accumulation of Ach within the brain. Ach is important for many brain functions including memory, so increasing concentration of this neurotransmitter can result in improved memory ⁶⁷⁾.

Positive effect on long-term memory has been demonstrated after administration of 35 g lecithin for 4 to 6 weeks ⁶⁸⁾. However, another report shows no improvement from lecithin in memory disorders when taken in 30 mg/day dosages ⁶⁹⁾.

Lecithin supplementation has also been studied in Alzheimer disease, starting with memory difficulties. Three of 7 Alzheimer patients receiving 25 g lecithin showed improvement in learning ability (coinciding with peak choline levels) ⁷⁰⁾. Combination tacrine and lecithin therapy conducted in a 32-patient double-blinded trial yielded poor results ⁷¹⁾. In a multicenter study, this combination did not improve mental status in 67 Alzheimer patients ⁷²⁾.

Acetylcholine deficiencies are also associated with other neurological disorders including tardive dyskinesia, Huntington chorea, Friedreich ataxia, myasthenia gravis, and other brain atrophies. In 2 patients with tardive dyskinesia, lecithin administration reduced abnormal movements. Ten cases of Friedreich ataxia were also improved by lecithin supplementation ⁷³⁾. One study failed to show any beneficial response in 12 patients with Friedreich ataxia taking 25 g lecithin daily ⁷⁴⁾.

Liver disease

In Germany, a product called Essentiale (phosphatidylcholine) is marketed for liver disorders including acute and chronic hepatitis, cirrhosis, diabetic fatty liver, and toxic liver damage. However, there are no clinical data regarding the use of lecithin for liver disease.

Other uses

Lecithin has also been used for immune modulation, activating specific and nonspecific defense systems in 20 patients receiving 1 teaspoonful 3 times daily for 30 days ⁷⁵⁾. Another report discusses gallstone dissolution in 2 of 7 patients treated with lecithin and oral cholic acid. One patient experienced stone size reduction ⁷⁶⁾.

Lecithin dosage

Most previous studies ⁷⁷⁾, ⁷⁸⁾, ⁷⁹⁾ have used the dosage of 1 to 3 g per day of oral supplementation of lecithin, exhibiting its effects for inflammatory diseases, hyperlipidemia, cardiovascular diseases, cognitive impairment, and fatiguing illnesses. Oral administration of lecithins has been shown to be generally safe ⁸⁰⁾. For example, in phase I and II clinical trials in patients with cardiovascular diseases, over 5 g of soy lecithins were administered with no apparent toxicity ⁸¹⁾. Referring to older studies, a daily dosage of as much as 54 g has been administered without any apparent adverse effects ⁸²⁾. Regarding the duration of the treatment, most of the previous studies investigating the effects of dietary lipid replacement therapy supplement on fatigue examined for 8 weeks, meanwhile some examined for 1 or 12 weeks ⁸³⁾.

Lecithin side effects

Although not all side effects are known, lecithin is thought to be likely safe for most people.

Common side effects may include anorexia, nausea, increased salivation, diarrhea, abdominal pain or fullness. However, there have been reports of hepatitis.

This is not a complete list of side effects and others may occur. Call your doctor for medical advice about side effects.

What is alpha lipoic acid

Alpha-Lipoic Acid also called thioctic acid or 1,2-dithiolane-3-pentanoic acid (pentanoic acid), is a naturally occurring short chain fatty acid which contains a thiol bond, synthesized in small amounts by plants and animals (including humans), with antioxidant and potential chemopreventive activities ¹⁾. Chemically, alpha lipoic acid is a short-chain fatty acid with a disulfide group in its dithiolane ring and a chiral carbon resulting in R and S enantiomers (see Figure 1 below). Although the majority of the commercially produced alpha lipoic acid consists of a racemic admixture, the R form, (R)-α-Lipoic acid, is the biologically active form that is endogenously produced by the body, while the S form is produced from chemical manufacture and is not biologically active ²⁾. Only R-α-Lipoic acid is conjugated to conserved lysine residues in an amide linkage, thus making this isoform essential as a cofactor in biological systems ³⁾. At the cellular level, alpha lipoic acid is reduced to dihydrolipoic acid (DHLA), which has a number of cellular actions including free radical scavenging and modulating oxidative stress and inflammatory pathways ⁴⁾. Alpha lipoic acid, when exogenously administered, is readily absorbed from the gut and has been clinically used in Europe for the treatment of diabetic polyneuropathy ⁵⁾.

Though in body synthesis appears to supply all the necessary alpha lipoic acid needed for its role in intermediary metabolism, alpha lipoic acid can also be absorbed from the diet ⁶⁾. While the direct roles of alpha lipoic acid as a cofactor are well understood, less is known about the precise metabolic functions of orally supplied alpha lipoic acid.

Figure 1. Alpha lipoic acid R and S enantiomers

Alpha-lipoic acid acts as a free radical scavenger and assists in repairing oxidative damage and regenerates endogenous antioxidants, including vitamins C and E and glutathione. Alpha lipoic acid also promotes glutathione synthesis. In addition, alpha-lipoic acid exerts metal chelating capacities and functions as a cofactor for energy production in the mitochondria in various mitochondrial enzyme complexes involved in the decarboxylation of alpha-keto acids and thus serves a critical role in mitochondrial energy metabolism ⁷⁾.

In addition to alpha-lipoic acid being made by your body, alpha-lipoic acid is also absorbed intact from dietary sources and can be found in almost all foods, but slightly more so in organ meats (kidney, heart, liver), spinach, broccoli, peas, brussel sprouts, and rice bran. Alpha-lipoic acid can also be made in the laboratory. Alpha-lipoic acid is biosynthesized by cleavage of linoleic acid and is a coenzyme of oxoglutarate dehydrogenase (ketoglutarate dehydrogenase complex).

Alpha lipoic acid is marketed in the US as an over-the-counter nutritional antioxidant supplement, alone or in combination with other antioxidants. In medicine, alpha lipoic acid has been shown to reduce symptoms of diabetic polyneuropathy, and several clinical trials established some efficacy and an excellent safety profile in this patient population ⁸⁾.

Alpha-lipoic acid is a type of antioxidant and chemoprotective agent. Alpha-lipoic acid is an antioxidant — a substance the body can use to prevent or manage a tissue-damaging process called oxidative stress. Oxidative stress is a part of the diabetic neuropathy disease process. Alpha-lipoic acid also has been shown to reduce blood sugar levels. Alpha lipoic acid is being studied for its ability to protect normal cells from the side effects of chemotherapy and prevent peripheral neuropathy (numbness, tingling, burning, and weakness in the hands or feet) ⁹⁾. A few small clinical trials have tested the treatment effect of alpha-lipoic acid given either as a supplement or intravenously. People with diabetic neuropathy had reduced pain, improvements in nerve function tests and improvements in other clinical measures of diabetic neuropathy (Han T, Bai J, Liu W, et al. A systematic review and meta-analysis of α-lipoic acid in the treatment of diabetic peripheral neuropathy. European Journal of Endocrinology. 2012;167(4):465-471.)). But long-term studies are needed.

Alpha-lipoic acid is being studied for its effect on complications of diabetes, including diabetic macular edema (an eye condition that can cause vision loss) and diabetic neuropathy (nerve damage caused by diabetes).

• In a 2011 study of 235 people with type 2 diabetes, 2 years of supplementation with alpha-lipoic acid did not help to prevent macular edema ¹⁰⁾.
• A 2016 assessment of treatments for symptoms of diabetic neuropathy that included 2 studies of oral alpha-lipoic acid, with a total of 205 participants, indicated that alpha-lipoic acid may be helpful ¹¹⁾.

Alpha-lipoic acid supplements are generally considered safe when taken as recommended. However, toxicity might occur if you take this supplement when you have a significant thiamin (vitamin B-1) deficiency. Don’t use alpha-lipoic acid if you’re a heavy user of alcohol.

Alpha lipoic acid foods

Almost all foods contain alpha lipoic acid, but slightly more so in organ meats (kidney, heart, liver), spinach, broccoli, peas, brussel sprouts, and rice bran.

What is alpha lipoic acid used for

Alpha-lipoic acid for diabetic peripheral neuropathy

People with both types of diabetes develop multisystem complications ¹²⁾, one of the most frequent being diabetic peripheral neuropathy. Diabetic peripheral neuropathy has an estimated prevalence in the diabetic population of between 10% and 100% depending upon the data source and ascertainment methodology ¹³⁾.

Diabetic peripheral neuropathy is defined as “the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes” ¹⁴⁾. Diabetic peripheral neuropathy may be asymptomatic and insidious at onset. The most common symptom of diabetic peripheral neuropathy is neuropathic pain, which occurs in up to 50% of people with diabetic peripheral neuropathy and is the most frequent reason for seeking medical care ¹⁵⁾. Painful symptoms are varied and include pain, tingling, burning sensations, paresthesia, shooting or lancinating pains, aching, and contact pain (allodynia) provoked by clothing ¹⁶⁾.

Diabetic peripheral neuropathy can be classified clinically as either focal or diffuse. Diffuse disease can affect the sensorimotor or the autonomic nervous systems or both. Sensorimotor disease can involve large or small nerve fibers ¹⁷⁾, is usually predominantly sensory, and may be painful.

Distal symmetrical sensorimotor polyneuropathy is the most common form of diabetic peripheral neuropathy, with a reported prevalence in diabetes mellitus ranging from 28.5% to 45%, increasing with age and disease duration ¹⁸⁾. Distal symmetrical sensorimotor polyneuropathy represents a major cause of morbidity and the leading source of diabetes-related hospitalizations and non-traumatic amputations. It is also accountable for considerable physical disability, altered quality of life, and increased mortality ¹⁹⁾.

Diabetic peripheral neuropathy complications are also a major threat to the general well-being and quality of life of people with diabetes. Numbness caused by diabetic peripheral neuropathy, along with retinopathy and vestibular dysfunction, increase the risk of falls two- to three-fold compared to people without diabetic peripheral neuropathy ²⁰⁾. People with diabetic peripheral neuropathy are also seven times more likely to develop foot ulcerations ²¹⁾. Foot ulcerations further predispose to active or passive soft tissue infection, which can progress to bone infection and subsequent lower extremity amputation ²²⁾. Diabetic peripheral neuropathy, peripheral vascular disease, and soft tissue and bone deformity are serious complications that make diabetes the leading cause of lower extremity amputation ²³⁾.

Diabetic peripheral neuropathy symptoms are usually assessed using patient-reported outcome measures that quantify discomfort, sleep disturbances, and quality of life ²⁴⁾.

The pathophysiology of diabetic peripheral neuropathy is not fully understood, and very likely to be multifactorial (genetic, environmental, behavioral, metabolic, neurotrophic, and vascular) ²⁵⁾. Oxidative stress generated by excess free-radical formation or errors in antioxidant protection, or both, is thought to be important in the pathogenesis ²⁶⁾. Good glycemic control reduces the risk of developing diabetic peripheral neuropathy, but glycemic control is not always achievable and is usually not sufficient to halt diabetic peripheral neuropathy progression ²⁷⁾.

Diabetic peripheral neuropathy pathophysiology can mainly be explained as neural dysfunction caused by the interplay of decreased blood flow to nerves as a result of hyperglycaemia, and increased oxidative stress, which induces local inflammatory reactions through reactive oxygen species (ROS) ²⁸⁾. Prolonged hyperglycemia simultaneously activates multiple pathways. It promotes the following:

• Activation of polyol and protein kinase pathways that leads to reduced nicotinamide adenine dinucleotide phosphate (NADPH) and subsequent depletion of glutathione and nitric oxide ²⁹⁾.
• Angiogenesis driven by the vascular endothelial growth factor pathway.
• Basement membrane thickening and endothelial proliferation (via transforming growth factor-β and nuclear factor – kappa B), which cause altered capillary permeability and local hypoxia.
• Activation of the hexosamine pathway and shunting of fructose-6-phosphate from the glycolytic pathway.
• Modified gene expression for glucose transporters and glucokinase ³⁰⁾.

Generation of reactive oxygen species and advanced glycosylation end-products activates the same NFkB pathway, which increases oxidative stress with additional nicotinamide adenine dinucleotide phosphate (NADPH) depletion. Oxidative stress also induces poly (ADP-ribose) polymerase activation, which sequentially results in supplementary nicotinamide adenine dinucleotide depletion, positive loop activation of the protein kinase pathway, and promotes inflammation ³¹⁾. All these pathways promote mitochondrial dysfunction, which in turn is followed by apoptosis, axonal degeneration, and axonal death. Local pro-inflammatory cytokines induced by oxidative stress promote macrophage recruitment with subsequent glial failure, myelin breakdown, and impaired nerve regeneration ³²⁾.

The clinical consequences of this hyperglycemia-induced inflammatory and oxidative state are axonal dystrophy, decreased nerve conduction velocity, diminished neurovascular flow and, ultimately, small- and large-fiber neuropathy ³³⁾.

Current management of diabetic peripheral neuropathy consists of three therapeutic approaches. The main target is prevention, through control of fasting and postprandial glucose ³⁴⁾. Medications that target symptoms and disease-modifying treatments are used in the treatment of people with diagnosed diabetic peripheral neuropathy. Symptomatic treatments target pain; they include anticonvulsants, tricyclic antidepressants ³⁵⁾, serotonin and noradrenaline reuptake inhibitors ³⁶⁾, opioids and opioid-like drugs ³⁷⁾, systemic local anaesthetics ³⁸⁾, nonsteroidal anti-inflammatory agents ³⁹⁾, and non-drug therapies such as transcutaneous electrical nerve stimulation (TENS), pulsed radiofrequency sympathectomy ⁴⁰⁾, and acupuncture ⁴¹⁾.

Disease-modifying treatments aim to prevent, slow, or reverse diabetic peripheral neuropathy progression by reduction of oxidative stress and inhibition of the polyol, hexosamine, protein kinase, advanced glycosylation product, and poly (ADP-ribose) polymerase pathways.

Alpha lipoic acid acts as a scavenger of reactive oxygen species and has antioxidant properties that could block the oxidative stress–inflammation pathways activated in diabetic peripheral neuropathy ⁴²⁾. Alpha lipoic acid could therefore be useful both in prevention and treatment of diabetic peripheral neuropathy ⁴³⁾.

Early in test tube studies showed that alpha lipoic acid and its reduced form, dihydrolipoic acid (DHLA), scavenge reactive oxygen species, including hydroxyl radicals, hypochlorous acid, and singlet oxygen ⁴⁴⁾. In animal studies also indicated that alpha lipoic acid decreases oxidative stress ⁴⁵⁾, participates in restoring endogenous cellular antioxidant levels and reducing pro-inflammatory pathways ⁴⁶⁾ and may influence the regeneration of vitamins C and E ⁴⁷⁾.

The benefit of alpha lipoic acid in people with diabetes could range beyond antioxidant and anti-inflammatory effects. The therapeutic properties of alpha lipoic acid might include the ability to restore glucose availability and increase insulin-stimulated glucose transport and non-oxidative and oxidative glucose metabolism in insulin-resistant muscle cells ⁴⁸⁾. Alpha lipoic acid has therefore been a candidate for clinical study in diabetic peripheral neuropathy.

The interaction of alpha lipoic acid with regulatory components of the insulin signaling cascade has proved functionally beneficial to skeletal muscle glucose uptake, whole-body glucose tolerance, and helpful against insulin resistance in animal models ⁴⁹⁾. Improvements in glucose disposal were also observed in human patients with type 2 diabetes receiving alpha lipoic acid either intravenously or orally ⁵⁰⁾. Several clinical trials have been conducted to measure the efficacy of racemic alpha lipoic acid in decreasing symptoms of diabetic polyneuropathies; these are the “alpha-lipoic acid in diabetic neuropathy” (Aalpha lipoic acidDIN) trials and the “symptoms of diabetic polyneuropathy” (SYDNEY) trials. alpha lipoic acid was given orally, intravenously, or i.v. with oral follow-up. A meta-analysis of four clinical trials using i.v. alpha lipoic acid, including Aalpha lipoic acidDIN, SYDNEY, and the first 3 weeks of Aalpha lipoic acidDIN III, showed a significant improvement in diabetic polyneuropathies of the feet and lower limbs in patients infused with alpha lipoic acid 600 mg/day, for three weeks ⁵¹⁾. Diabetic patients in the Aalpha lipoic acidDIN II trial were administered alpha lipoic acid i.v. at 600 or 1200 mg/day for 5 days, then oral alpha lipoic acid for 2 years, resulting in improved indices of neuropathy ⁵²⁾. Patients in the Aalpha lipoic acidDIN III study received alpha lipoic acid (600 mg/day i.v.) or placebo for three weeks, followed by oral alpha lipoic acid (600 mg t.i.d.) or placebo for 6 months. The oral phase of this trial, however, was without clinically significant benefits ⁵³⁾. One possible conclusion from these studies was that alpha lipoic acid administered intravenously was more efficacious than oral alpha lipoic acid, which may be due to either greater bioavailability or poor solubility of the medication in the stomach acid. However, some additional studies have found that oral alpha lipoic acid is very effective. For example, the oral pilot (ORPIL) study showed a reduction in diabetic polyneuropathic symptoms after three weeks with 600 mg alpha lipoic acid three times daily ⁵⁴⁾. While the first SYDNEY trial used i.v. alpha lipoic acid ⁵⁵⁾, the SYDNEY II study used oral alpha lipoic acid at 600, 1200, or 1800 mg once daily for 5 weeks ⁵⁶⁾; consequently, both studies showed significant improvements in neuropathic endpoints.

Alpha lipoic acid and weight loss

Previous studies have suggested anti-obesity properties of alpha lipoic acid ⁵⁷⁾, ⁵⁸⁾. In animal studies, it was shown that alpha lipoic acid supplementation promotes the reduction of body weight and fat mass by decreasing food intake and enhancing energy expenditure, possibly by suppressing hypothalamic AMP-activated protein kinase (AMPK) activity ⁵⁹⁾. However, studies in humans with alpha lipoic acid supplementation are limited, and the results have been inconsistent. Some clinical trials have shown that alpha lipoic acid supplementation may help overweight or obese individuals lose weight ⁶⁰⁾, while other studies have observed no effects of alpha lipoic acid on weight ⁶¹⁾, ⁶²⁾. Nevertheless, alpha lipoic acid appears to have a wide range of beneficial effects on obesity related conditions such as insulin resistance, metabolic syndrome, and type II diabetes, including their complications such as vascular damage ⁶³⁾.

Cumulative results in a 2017 meta-analysis showed significant reduction of body weight and BMI (body mass index) with alpha lipoic acid treatment compared to placebo, regardless if it was used for weight loss or other purposes ⁶⁴⁾. Small but significant reduction of body weight with alpha lipoic acid intervention is in line with previous open label studies that have well documented the effectiveness of alpha lipoic acid on weight loss in overweight and obese individuals ⁶⁵⁾, ⁶⁶⁾ and randomized studies ⁶⁷⁾, ⁶⁸⁾, ⁶⁹⁾, ⁷⁰⁾. These results conclude that alpha lipoic acid supplementation with diet intervention may provide more beneficial effects on body weight management in overweight and obese individuals.

Studies in the 2017 meta-analysis explored various doses of alpha lipoic acid intervention (300 mg/day to 1800 mg/day) on different intervention durations (8 weeks to 52 weeks). Only one placebo controlled study compared the effectiveness of different doses of alpha lipoic acid on body weight ⁷¹⁾. Koh et al. ⁷²⁾ explored the effects of 1200 mg/day and 1800 mg/day alpha lipoic acid intervention on body weight loss. Koh et al. ⁷³⁾ found that the higher dose of alpha lipoic acid resulted in significant weight loss and BMI reduction throughout the study compared to placebo. The lower dose of alpha lipoic acid led to significant weight loss in the first weeks of this study, however this effect was not sustainable through the entire duration of the study. From these findings, it can argue that the effect of alpha lipoic acid on body weight is limited to the short term, especially when it is used at lower doses with an adaptation mechanism taking over later. This may have implications for future study designs, for example phasic use of the medication may be tried ⁷⁴⁾.

In summary, findings from 2017 ⁷⁵⁾ and 2018 meta-analyses ⁷⁶⁾ suggest that alpha lipoic acid may be a useful supplementation for weight loss in overweight and obese individuals in reducing body weight and BMI, but has no significant effect on waist circumference. The benefits of alpha lipoic acid compared to placebo appear smaller than that of available prescription weight loss medications ⁷⁷⁾. However, alpha lipoic acid can be considered in clinical practice due to its benign side-effect profile, other beneficial effects such as in diabetic neuropathy, and lower side effects comparing to the available weight loss medications. Further research is needed to examine the effect of different doses and the long-term benefits of alpha lipoic acid on metabolic parameter in unhealthy obese individuals.

Alpha lipoic acid benefits

Effects of alpha lipoic acid on the vascular system

Vascular endothelial cells, which line the blood vessel lumen, form the physical interface between the blood and the vessel wall, preventing platelet adhesion and regulating blood vessel patency. The elasticity of the vessel wall is regulated by nitric oxide (NO), a gas produced by endothelial nitric oxide synthase (eNOS). Loss of endothelial nitric oxide synthase (eNOS) activity causes endothelial dysfunction due to nitric oxide (NO) limitation, and is characterized by reduced vasodilation, a proinflammatory milieu, and a prothrombic state. Oxidative stress has been implicated in endothelial dysfunction on the basis that antioxidants, such as ascorbate and alpha lipoic acid, improve the redox state of the plasma and endothelium-dependent nitric oxide (NO)-mediated vasodilation ⁷⁸⁾. But the question remains as to how alpha lipoic acid achieves this significant result. It is known, for instance, that the PI3K/Akt signaling pathway, cascading from the insulin receptor and stimulated by alpha lipoic acid, plays an important role in eNOS activation ⁷⁹⁾. Treating human aortic endothelial cells with alpha lipoic acid significantly increases NO synthesis ⁸⁰⁾, and alpha lipoic acid improves the loss in eNOS phosphorylation seen in aorta from aged rats through Akt ⁸¹⁾. Furthermore, i.p. injection of alpha lipoic acid into old rats restores vasorelaxation, characterized by an increased phosphorylation of both eNOS and Akt, as well as a decrease in neutral sphingomyelinase activity and a concomitant decrease in ceramide ⁸²⁾. These studies using in vitro and animal models strengthen our understanding of the role of the insulin signaling pathway in vasomotor function, and underscore the health potential of alpha lipoic acid therapy. Thus far, however, only the ISalpha lipoic acidND (ISLAND) clinical trial has examined alpha lipoic acid as a potential remedy for endothelial dysfunction ⁸³⁾. This trial was a randomized, double-blind, placebo-controlled study comparing alpha lipoic acid to irbesartan, an angiotensin II receptor antagonist used mainly for the treatment of hypertension. Results showed that the oral administration of alpha lipoic acid (300 mg/day for 4 weeks) and/or irbesartan (150 mg/day for 4 weeks) to 14-15 patients with metabolic syndrome improved endothelial-dependent flow-mediated vasodilation, which was measured by using the noninvasive brachial artery reactivity test. However, larger and more long-term studies are necessary in order to establish the efficacy of alpha lipoic acid as a therapeutic for vascular endothelial dysfunction.

Alpha lipoic acid as a hypotensive agent

Hypertension is a risk factor for stroke, heart attack and arterial aneurysm, and a leading cause of chronic kidney failure. Even moderate elevation in arterial blood pressure correlates with shortened life expectancy. The rationale for the therapeutic use of alpha lipoic acid against hypertension stemmed from its ability to increase tissue GSH levels and prevent deleterious sulfhydryl group modification in Ca2+ channels. Feeding alpha lipoic acid to hypertensive rats normalized systolic blood pressure and cytosolic free Ca2+, and attenuated adverse renal vascular changes ⁸⁴⁾. The role of alpha lipoic acid in regenerating reduced GSH was further put forth by El Midaoui and de Champlain ⁸⁵⁾ who associated the restoration of glutathione peroxidase activity seen in alpha lipoic acid-fed rats with the normalization of aortic superoxide production and blood pressure. It was also suggested that dietary alpha lipoic acid inhibits renal and vascular overproduction of endothelin-1, a vasoconstrictor secreted by the endothelium ⁸⁶⁾. Because NO is the main vasodilator in conduit arteries and the recent finding that alpha lipoic acid improves endothelial NO synthesis ⁸⁷⁾, pharmacologists have a new rationale to investigate the role of alpha lipoic acid and high blood pressure. Clinically, alpha lipoic acid administration (in combination with acetyl-L-carnitine) showed some promise as an antihypertensive therapy by decreasing systolic pressure in high blood pressure patients and subjects with the metabolic syndrome ⁸⁸⁾. In contrast, the administration of alpha lipoic acid (300 mg/day for 4 weeks) to patients with the metabolic syndrome had no significant effect on blood pressure compared to placebo group ⁸⁹⁾.

Alpha lipoic acid as an anti-inflammatory agent

Inflammation results from the innate biological response of vascular tissues to harmful agents, such as pathogens or irritants. It is an attempt by the organism to remove the injurious stimuli, protect the surrounding tissue, and initiate the healing process. However, unabated chronic inflammation also contributes to a host of diseases, such as atherosclerosis, asthma, and rheumatoid arthritis. Elevated levels of oxidative stress play an important role in chronic inflammation. Oxidative stress-associated inflammation is thought to provoke early vascular events in atherogenesis, including the upregulation of vascular adhesion molecules and matrix metalloproteinase activity. These events require the activation of NF-kappaB, a transcription factor that induces expression of many genes involved in inflammation and endothelial cell migration. Given the oxidative nature of inflammation, therapeutic strategies aimed at mitigating oxidant production and oxidative damage have been investigated for decades in various models of inflammation.

In keeping with this strategy, alpha lipoic acid has been studied for its antioxidant properties in cytokine-induced inflammation; it is also widely known as an inhibitor of NF-kappaB ⁹⁰⁾. Results show that alpha lipoic acid lowers expression of vascular cell adhesion molecule-1 (VCAM-1) and endothelial adhesion of human monocytes ⁹¹⁾, and inhibits NF-kappaB-dependent expression of metalloproteinase-9 in vitro ⁹²⁾. Similarly, alpha lipoic acid (25-100 μg/ml = 122-486 μM) prevents the upregulation of intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in spinal cords and in TNF-alpha stimulated cultured brain endothelial cells ⁹³⁾. Collagen-induced arthritis was attenuated by alpha lipoic acid (10-100 mg/kg i.p.) in DBA/1 mice by reduction of inflammatory cytokines like TNF-alpha, and partial inhibition of NF-kappaB binding to DNA ⁹⁴⁾. In this study, alpha lipoic acid also inhibited osteoclast formation, suggesting that alpha lipoic acid may be useful in the prevention of bone erosion and joint destruction in rheumatoid arthritis. In another study, pretreatment of collagen sheets with alpha lipoic acid (2 mg) prior to implantation decreased TNF-alpha-induced bone resorption in ICR mice ⁹⁵⁾. In experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis) alpha lipoic acid-treated mice showed marked improvement in central nervous system infiltrating T-cells and macrophages, decreased demyelination and spinal cord expression of adhesion molecules (ICAM-1 and VCAM-1) ⁹⁶⁾. The downregulation of surface CD4 seen in alpha lipoic acid-treated blood mononuclear cells was proposed to account, at least in part, for the modulation of inflammatory cell infiltration into the central nervous system ⁹⁷⁾. This is because co-receptor CD4 amplifies the signal generated at the T-cell receptor by recruiting lymphocyte protein kinase Lck, which in turn triggers a cascade of events leading to T-cell activation. Interestingly, DHalpha lipoic acid did not downregulate CD4 from the surface of human peripheral blood mononuclear cells ⁹⁸⁾. As an alternative or in addition to CD4 downregulation, the immunomodulatory properties of alpha lipoic acid may involve the upregulation of cAMP in T-cells and natural killer cells ⁹⁹⁾. Cell migration and neovascularization were also inhibited by alpha lipoic acid (86 μg/day in drinking water) in c57/black mice injected with Kaposi’s sarcoma in a matrigel sponge, as well as in nude mice injected with KS cells ¹⁰⁰⁾. In a mouse model of bronchial asthma, dietary alpha lipoic acid significantly attenuated airway hyper-responsiveness, lowered the eosinophil count among bronchoalveolar lavage cells, and significantly improved pathologic lesion scores of the lungs ¹⁰¹⁾. alpha lipoic acid inhibits TNF-alpha-induced NF-kappaB activation and adhesion molecule expression in human aortic endothelial cells via a mechanism seemingly distinct from antioxidants, such as ascorbate or reduced GSH, but consistent with the workings of a metal chelator ¹⁰²⁾. Recently, the inhibition of endotoxin-induced acute inflammation by alpha lipoic acid was associated with the stimulation of the PI3K/Akt pathway ¹⁰³⁾.

To date, the anti-inflammatory properties of alpha lipoic acid have rarely been investigated in humans. The ISalpha lipoic acidND (ISLAND) trial showed a 15% significant decrease in serum interleukin-6 levels following 4 weeks of supplementation with alpha lipoic acid (300 mg/day) ¹⁰⁴⁾. This finding may prove important to human health because interleukin-6 is a recognized marker of inflammation in coronary atherosclerotic plaques, and also regulates the expression of other inflammatory cytokines, such as interleukin-1 and TNF-alpha ¹⁰⁵⁾. However, the body of evidence is currently too limited to be conclusive.

Alpha lipoic acid dosage

Clinical trials have used different forms of administration and treatment durations. Alpha lipoic acid dosage ranges from 200 mg/day to 1800 mg/day, administered intravenously or orally. Although the maximum dose of alpha lipoic acid has not been defined, previous studies have shown that alpha lipoic acid can be used safely up to as high as 1800 mg/day ¹⁰⁶⁾.

However, despite the evidence attesting to its safety in moderate doses, precautions for the oral intake of alpha lipoic acid have also been voiced. Cakatay et al. ¹⁰⁷⁾ conducted a series of experiments in aged rats with intraperitoneal administration of racemic alpha lipoic acid (100 mg/kg body weight per day for 2 weeks) and showed that this high chronic dose (the equivalent of 5 to 10 grams per day in humans) increased plasma lipid hydroperoxide levels and oxidative protein damage ¹⁰⁸⁾. Alpha lipoic acid-mediated protein damage was noted in rat heart ¹⁰⁹⁾ and brain ¹¹⁰⁾, but lipid hydroperoxide levels were beneficially decreased in both these organs. Apparently in keeping with its metal chelating abilities, this group noted that alpha lipoic acid lowered selenium levels in the serum, heart, brain, and muscle; manganese was lowered only in the heart, but increased in the brain and muscle ¹¹¹⁾. Thus, while intake of moderate doses of alpha lipoic acid have relatively few adverse side-effects, alpha lipoic acid may mediate oxidative insult at higher doses or when administered intraperitoneally. More research is therefore warranted regarding both the safety and optimal dose of alpha lipoic acid.

Alpha lipoic acid side effects

The most commonly reported side effects that were related with alpha lipoic acid in these two studies ¹¹²⁾, ¹¹³⁾ were gastrointestinal symptoms, such as abdominal pain, nausea, vomiting, and diarrhea ¹¹⁴⁾ and dermatological symptoms, such as urticaria and itching sensation. One subject in the 1800 mg/d alpha-lipoic acid group and 3 subjects in the 1200 mg/d alpha-lipoic acid group withdrew because of itching sensation ¹¹⁵⁾.

What is yerba mate

Yerba mate (Ilex paraguariensis A.St.-Hil., Aquifoliaceae) is a native tree growing in the subtropics of South America, present in Southern Brazil, Northeastern Argentina, Eastern Paraguay, and Uruguay ¹⁾. Toasted yerba mate tea is an herbal infusion obtained from dried leaves of Ilex paraguariensis ²⁾. Yerba mate is traditionally consumed either as hot yerba mate or cold yerba mate. The hot yerba mate infusion consumed in South America is made by placing 20–50 g of yerba mate in a vessel where very hot water (70–85 °C) is slowly poured over the material and after each pouring, the water is sucked through a special drinking straw fitted with a filter on the end immersed in the mate infusion ³⁾. Cold yerba mate may be consumed in the same way or in a glass like a regular drink, at 4–8 °C ⁴⁾. Polycyclic aromatic hydrocarbons in mate are produced by fire or high temperature exposure during traditional drying using direct fire and/or during roasting of the mate leaves ⁵⁾. The commercial processing of yerba mate may involve two successive drying stages namely an initial rapid drying process at 400–750 °C by use of direct flames followed by final drying at 90–350 °C in rotating cylinders heated by burning wood before grinding ⁶⁾.

It is believed that consumption of Yerba mate is associated with increased risk of oral cancer ⁷⁾, esophageal cancer ⁸⁾, cancer of the larynx ⁹⁾ and squamous cell cancers of the head and neck ¹⁰⁾, but the carcinogenic mechanism is unclear ¹¹⁾, ¹²⁾. Commercial brands of Yerba mate contain high levels of carcinogenic polycyclic aromatic hydrocarbons, which are acquired during the traditional drying process. Some authors believe that it’s the very hot (> 65 °C) Yerba mate beverages is probably associated with increased risk of oesophageal cancer ¹³⁾, ¹⁴⁾, whilst others believe it’s the high levels of carcinogenic polycyclic aromatic hydrocarbons from drinking Yerba mate ¹⁵⁾ as measured from increased urinary concentrations of some polycyclic aromatic hydrocarbon metabolites in Yerba mate drinkers which is as much as smoking cigarettes. While it is true that the temperature of hot infusions may influence the risk of esophageal squamous cell carcinoma ¹⁶⁾, ¹⁷⁾, ¹⁸⁾, the polycyclic aromatic hydrocarbon content in Yerba mate is not affected by the water temperature ¹⁹⁾. These results confirm that drinking yerba mate is a source of exposure to potentially carcinogenic polycyclic aromatic hydrocarbons, consistent with the hypothesis that the polycyclic aromatic hydrocarbon content of Yerba mate may contribute to the increased risk of esophageal squamous cell carcinoma in Yerba mate drinkers.

While the epidemiological data indicate that Yerba mate users have an increased risk of oral and oro-pharyngeal cancer, little is known about whether this increased risk is due to the high temperature of the beverage when it is consumed or due to certain carcinogenic constituents that are present in Yerba mate. More human and animal studies are needed before a conclusion can be made on the oral and oro-pharyngeal carcinogenic risk of Yerba mate to humans.

The yerba mate beverage has been consumed traditionally by Guarani indigenous people since before the conquest of South America by the Spaniards ²⁰⁾. The commercial potential of Yerba mate plant was discovered by the Jesuits, who brought wild growing yerba mate into cultivation. The Guarani name for yerba mate is ka’a which means “a plant” or “a herb”; hence yerba mate has been considered by this group as the plant par excellence ²¹⁾. Yerba mate was also known as Jesuit tea or Paraguayan tea and shipped as such to Europe ²²⁾. With the expulsion of the Jesuits in 1768, the plantations went wild. By this time, the yerba mate beverage was already popular among Mestizo people (of Spanish and Guarani origin). Since the end of the 19th century, Yerba mate also became a daily beverage for the European migrants who partly colonized Southern Brazil, Northeastern Argentina, and, to a lesser extent, Eastern Paraguay ²³⁾. Nowadays yerba mate is consumed at the rate of more than one liter per day by millions of people in the above-mentioned countries ²⁴⁾. Yerba mate is used both as a source of caffeine, in lieu or in parallel with tea and coffee, but also as a therapeutic agent for its alleged pharmacological properties ²⁵⁾. Caffeine (1,3,7-trimethylxanthine) is an alkaloid that occurs naturally in the leaves, seeds and fruit of tea, coffee, cacao, kola trees, yerba mate and more than 60 other plants ²⁶⁾. When ingested, caffeine is a central nervous system stimulant and can temporarily increase blood pressure and heart rate ²⁷⁾. Yerba mate plays a very special social role and constitutes a very important form of caffeine intake ²⁸⁾. Its popularity is also increasing outside South America due to its pharmacological properties, proven to be beneficial to health ²⁹⁾. Yerba mate also a very important drink in Syria and Lebanon due to Syro-Lebanese migration to Argentina in the second half of the 19th century. Many migrants who returned to the Levant in the 1920s took the habit of drinking Yerba mate with them ³⁰⁾.

Using liquid chromatography–mass spectrometry analysis on four commercial brands of yerba mate, 58 polyphenols were observed of which 4-sinapoylquinic acid, di- and tri-methoxycinnamoylquinic acids, two isomers of trimethoxycinnamoylshikimic acid and four isomers of caffeoyl-2,7-anhydro-3-deoxy-2-octulopyranosonic acid were identified for the first time in Yerba mate ³¹⁾. Additionally, 46 polyphenols and 2 methylxanthines were quantified by high-performance liquid chromatography with diode-array detection. Hydroxycinnamic acid derivatives and flavonols comprised 90% and 10% of yerba mate phenols, respectively, 3-caffeoylquinic (26.8-28.8%), 5-caffeoylquinic (21.1-22.4%), 4-caffeoylquinic (12.6-14.2%) and 3,5-dicaffeoylquinic acids (9.5-11.3%) along with rutin (7.1-7.8%) were the most abundant polyphenols, whereas caffeine was the main methylxanthine (90%). Yerba mate is an important source of polyphenols with moderate methylxanthines content; therefore its high antioxidant capacity was mainly associated to its polyphenolic composition.

Yerba mate (Ilex paraguariensis) has antioxidant properties due to its phenolic compounds, such as caffeoyl derivatives, flavonoids, methylxanthines, tannins, ursolic acid-derived saponins, and vitamins ³²⁾. Over the last 20 years there has been an increase in studies of the pharmacologic properties of Yerba mate (Ilex paraguariensis). Numerous active compounds have been identified in yerba mate. Phenolic compounds predominate caffeoyl derivatives (caffeic acid, chlorogenic acid) ³³⁾, xanthines (caffeine and theobromine), which are a class of purine alkaloids found in many other plants such as tea and coffee, flavonoids (quercetin, kaempferol, and rutin), and tannins ³⁴⁾. Numerous triterpenoid saponins have also been identified, including those derived from ursolic acids known as metasaponins ³⁵⁾. Saponins are responsible for the distinct flavor of yerba mate extracts ³⁶⁾. Yerba mate also contains minerals (Phosphorus, Iron, and Calcium) and vitamins (C, B1, and B2) ³⁷⁾.

Research on extracts and isolated compounds from yerba mate has provided a number of pharmacological applications. Studies have demonstrated that yerba mate leaves have antioxidant ³⁸⁾, antiobesity ³⁹⁾, antidiabetic, digestive improvement and cardiovascular properties ⁴⁰⁾, and chemopreventative ones (preventing cellular damage that may cause chronic diseases) ⁴¹⁾. The consumption of yerba mate infusion reduces LDL “bad” cholesterol in parallel with an increase in HDL “good” cholesterol, as observed in studies on humans ⁴²⁾. Yerba mate extract also reduces acute lung inflammation, as observed in the animal model ⁴³⁾. Antimicrobial activity of yerba mate has been recently studied as well ⁴⁴⁾.

Some ethnobotanical studies from South America report medicinal uses of yerba mate beverage ⁴⁵⁾. Few ethnobotanical and ethnopharmacological studies mention that various medicinal plants are consumed together with the yerba mate beverage by Mestizo and European migrants living in Argentina and Paraguay ⁴⁶⁾. However, very little is known about how medicinal plants are combined with yerba mate beverage by local people. Additionally, medicinal plant use by Paraguayan Mestizo people is poorly documented in the English-language scientific literature, with very few exceptions ⁴⁷⁾.

Is Yerba mate safe to drink?

Yerba mate isn’t likely to pose a risk for healthy adults who occasionally drink it. However, some studies indicate that people who drink large amounts of yerba mate over prolonged periods may be at increased risk of some types of cancer, such as cancer of the mouth, esophagus and lungs. Smoking in combination with yerba mate seems to greatly increase the cancer risk.

One possible explanation is that mate contains polycyclic aromatic hydrocarbons (PAHs), which are known to be carcinogenic. Tobacco smoke and grilled meat also contain polycyclic aromatic hydrocarbons. Whilst others believe it is very hot Yerba mate beverages that probably causes cancer of the esophagus in humans. More investigation needs to be done into the safety and side effects of Yerba mate.

In summary: The epidemiological data indicate that Yerba mate users have an increased risk of oral and oro-pharyngeal cancer, little is known about whether this increased risk is due to the high temperature of the beverage when it is consumed or due to certain carcinogenic constituents that are present in Yerba mate ⁴⁸⁾. More human and animal studies are needed before a conclusion can be made on the oral and oro-pharyngeal carcinogenic risk of maté to humans.

Figure 1. Yerba mate

Figure 2. Yerba mate gourd

What is Caffeine ?

Caffeine (1,3,7-trimethylxanthine) is an adenosine and benzodiazepine receptor antagonist, phosphodiesterase inhibitor, and central nervous system stimulant ⁴⁹⁾, ⁵⁰⁾. Caffeine is a pharmacologically active component of many foods, beverages, dietary supplements, and drugs; it is also used to treat very ill newborns afflicted with apnea (temporary cessation of breathing) ⁵¹⁾. Caffeine occurs naturally in some plant leaves, seeds, and fruits, where it serves as an herbicide, insect repellant, and even attractant for pollination ⁵²⁾. This botanically sourced compound is the most commonly consumed stimulant worldwide ⁵³⁾. Caffeine enters the human food chain through plant-derived foods such as coffee beans, tea leaves, guarana, cocoa beans, yerba mate and kola nuts ⁵⁴⁾. In healthy adults, a caffeine intake of ≤400 mg/day is considered safe; acute clinical toxicity begins at 1 g, and 5 to 10 g can be lethal ⁵⁵⁾.

Caffeine is the world’s most popular drug, and coffee is possibly the second most valuable product after oil. The common dietary sources of caffeine are coffee, chocolate, tea, and some soft drinks. The amount of caffeine in food products varies, depending on the serving size, the type of product and the preparation method ⁵⁶⁾. Up to 90% of Americans of all ages consume some caffeine daily with more than 50% consuming coffee daily ⁵⁷⁾. More than 50% average 300mg caffeine per day, with an average daily dosage for all consumers of about 200mg. One report estimates nearly 95% of Brazil’s population consumes caffeine daily, whereas only about 63% of Canadian adults do so. The average dietary caffeine consumption in some Scandinavian countries is more than 400 mg per person per day. It is not hard to reach 200-300mg of caffeine daily since a standard eight-ounce cup of coffee made by the American drip method contains between 125mg and 250mg of caffeine. A 12-ounce can of Coca-Cola contains 34mg. Also, the usual ‘cup’ of coffee for many individuals is often actually 12 or even 16 ounces and sometimes more.

Most people consume caffeine from drinks. The amounts of caffeine in different drinks can vary a lot, but it is generally

• An 8-ounce cup of coffee: 95-200 mg
• A 12-ounce can of cola: 35-45 mg
• An 8-ounce energy drink: 70-100 mg
• An 8-ounce cup of tea: 14-60 mg

Caffeine has many effects on your body’s metabolism

• Caffeine stimulates your central nervous system, which can make you feel more awake and give you a boost of energy.
• Caffeine is a diuretic, meaning that it helps your body get rid of extra salt and water by urinating more.
• Caffeine increases the release of acid in your stomach, sometimes leading to an upset stomach or heartburn.
• Caffeine may interfere with the absorption of calcium in the body.
• Caffeine increases your blood pressure.

Within one hour of eating or drinking caffeine, it reaches its peak level in your blood. You may continue to feel the effects of caffeine for four to six hours.

For most people, it is not harmful to consume up to 400mg of caffeine a day. If you do eat or drink too much caffeine, it can cause health problems, such as:

• Restlessness and shakiness
• Insomnia. Most adults need seven to eight hours of sleep each night. But caffeine, even in the afternoon, can interfere with this much-needed sleep. Chronically losing sleep — whether it’s from work, travel, stress or too much caffeine — results in sleep deprivation. Sleep loss is cumulative, and even small nightly decreases can add up and disturb your daytime alertness and performance. Using caffeine to mask sleep deprivation can create an unwelcome cycle. For example, you may drink caffeinated beverages because you have trouble staying awake during the day. But the caffeine keeps you from falling asleep at night, shortening the length of time you sleep.
• Headaches
• Dizziness
• Rapid or abnormal heart rhythm
• Stomach upset
• Dehydration
• Anxiety
• Dependency, so you need to take more of it to get the same results.

Some people are more sensitive to the effects of caffeine than others. If you’re susceptible to the effects of caffeine, just small amounts — even one cup of coffee or tea — may prompt unwanted effects, such as restlessness and sleep problems. How you react to caffeine may be determined in part by how much caffeine you’re used to drinking. People who don’t regularly drink caffeine tend to be more sensitive to its negative effects. Other factors may include genetics, body mass, age, medication use and health conditions, such as anxiety disorders.

Do not underestimate the power or potency of caffeine. An abrupt decrease in caffeine may cause withdrawal symptoms, such as headaches, fatigue, irritability and difficulty focusing on tasks. Fortunately, these symptoms are usually mild and resolve after a few days. Caffeine dependency can occur after as little as seven days of exposure. 100mg per day can sustain dependency. In fact, many individuals can avoid caffeine withdrawal symptoms by as little as 25mg—the equivalent of about two tablespoons of most “gourmet” coffees. Carefully controlled studies show that caffeine doses as low as about 10mg can be reliably noticed by particularly sensitive people. These studies also show that more than 30 percent of people can feel the effects of 18mg or less.

Studies of caffeine dependency and tolerance show that daily caffeine users are actually more motivated to consume it to avoid withdrawal symptoms, than to experience the lift that its stimulant properties may provide. Caffeine’s combination of a punishing syndrome of withdrawal, along with a rewarding sense of wakefulness, has made coffee, tea, and chocolate, some of humanity’s best-loved foods. One might say that caffeine-producing plants have succeeded in motivating humans to cultivate them widely and with very great care.

Not everyone consuming daily caffeine is equally likely to develop dependency and withdrawal syndrome. Studies indicate that genetics make some people more likely than others. Scientists do not know whether the inherited tendency to experience caffeine withdrawal syndrome relates to the genetic factors that cause migraine. In summary, caffeine may lead to the development of medication-overuse headache (so-called “rebound” headache). As such, patients should limit caffeine use as recommended for other acute medications for migraine. This use should not exceed two days per week. Removing caffeine alone is rarely enough to solve the problem. For patients with high daily caffeine intake, this reduction in use should be achieved over a gradual taper of days or even weeks to limit the impact of withdrawal syndrome.

Does yerba mate have caffeine?

Yes, Yerba mate contains caffeine and other chemicals which stimulate the brain, heart, muscles lining blood vessels, and other parts of the body.

How much caffeine in yerba mate?

Because label instructions varied so widely among the products (from 1 tablet/day to 4 tablets/serving and 3 servings/day), Yerba mate has about 489 mg/day of caffeine based on the average analyzed caffeine content ⁵⁸⁾.

Yerba mate vs coffee

According to the USDA food composition database, one cup (8 oz, 240 ml) of brewed coffee contains approximately 95 mg of caffeine.

Coffee is a brewed drink prepared from roasted coffee beans, which are the seeds of berries from the Coffea plant. The genus Coffea is native to tropical Africa (specifically having its origin in Ethiopia and Sudan) and Madagascar, the Comoros, Mauritius, and Réunion in the Indian Ocean. Several species of shrub of the genus Coffea produce the berries from which coffee is extracted. The two main species commercially cultivated are Coffea canephora (predominantly a form known as ‘Robusta’) and Coffea Arabica ⁵⁹⁾. Coffea arabica, the most highly regarded species, is native to the southwestern highlands of Ethiopia and the Boma Plateau in southeastern Sudan and possibly Mount Marsabit in northern Kenya ⁶⁰⁾. Coffea canephora is native to western and central Subsaharan Africa, from Guinea to Uganda and southern Sudan ⁶¹⁾. Less popular species are Coffea liberica, Coffea stenophylla, Coffea mauritiana, and Coffea racemosa.

Once ripe, coffee berries are picked, processed, and dried. Dried coffee seeds (referred to as beans) are roasted to varying degrees, depending on the desired flavor. Roasted beans are ground and brewed with near-boiling water to produce coffee as a beverage.

The degree of roast has an effect upon coffee flavor and body. Darker roasts are generally bolder because they have less fiber content and a more sugary flavor. Lighter roasts have a more complex and therefore perceived stronger flavor from aromatic oils and acids otherwise destroyed by longer roasting times. Roasting does not alter the amount of caffeine in the bean, but does give less caffeine when the beans are measured by volume because the beans expand during roasting.

Roasted coffee beans contain 0.8–2.5% caffeine. Generally, dark-roast coffee has less caffeine than lighter roasts because the roasting process reduces the bean’s caffeine content. Arabica coffee normally contains less caffeine than the Robusta variety. In general, one serving of coffee ranges from 64 mg for a single cup (30 ml) of espresso to about 145 mg for an 8-oz. ounce cup (237 ml) of automatic drip coffee.

Yerba mate benefits

In foods, yerba mate is used to make a tea-like beverage. Some people take yerba mate by mouth to relieve mental and physical tiredness (fatigue), as well as chronic fatigue syndrome. Yerba mate is also taken by mouth for heart-related complaints including heart failure, irregular heartbeat, and low blood pressure.

Some people also take yerba mate by mouth to improve mood and depression; for diabetes; high cholesterol; weak bones (osteoporosis); to relieve headache and joint pains; to treat urinary tract infections (UTIs), and bladder and kidney stones; for weight loss; and as a laxative.

Yerba Mate beverages are reported to have biological activities, probably due to their high polyphenol content. Phenolic compounds have long been known to possess biological functions. In addition to polyphenols such as flavonoids (quercetin and rutin) and phenolic acids (chlorogenic and caffeic acids), Yerba Mate is also rich in caffeine and saponins ⁶²⁾. Yerba Mate extracts are especially rich in chlorogenic acids that might contribute to hypocholesterolemic ⁶³⁾ and weight loss effects ⁶⁴⁾. Chlorogenic acid inhibits adipogenesis by reducing the expression of genes regulating adipogenesis in 3T3-L1 cells and in mouse model of high fat diet-induced obesity ⁶⁵⁾. In these regards, it is likely that Yerba Mate may potential alternative for controlling body fat accumulation and weight. In vitro and in vivo studies have demonstrated that Yerba Mate modulates signaling pathways, has chemopreventive activities ⁶⁶⁾, enhance intestinal propulsion ⁶⁷⁾, has vasodilatation effects ⁶⁸⁾, inhibits glycation ⁶⁹⁾, inhibits oxidative stress ⁷⁰⁾ and has inflammatory effects ⁷¹⁾.

Currently there’s insufficient evidence to rate effectiveness of Yerba mate for these conditions:

• Mental function. Early research shows that drinking a beverage containing yerba mate does not improve memory, reaction time, or mental accuracy in healthy females.
• Diabetes. Early research shows that drinking yerba mate tea three times daily for 60 days can lower blood sugar in people with type 2 diabetes.
• High cholesterol (hyperlipidemia). Early research shows that drinking tea containing yerba mate three times daily for 40 days can lower total cholesterol and low-density lipoprotein (LDL or “bad”) cholesterol, and increase high-density lipoprotein (HDL or “bad”) cholesterol, in people with high cholesterol. This includes people already taking statin drugs.
• Obesity. Early research shows that taking yerba mate by mouth might decrease fat and cause weight loss when used alone or in combination with guarana and damiana.
• Weak bones (osteoporosis). Drinking yerba mate tea every day for at least 4 years might reduce the rate of bone loss in postmenopausal women.
• Prediabetes. Early research shows that drinking yerba mate tea three times daily for 60 days does not reduce fasting blood sugar in people with prediabetes. However, it might reduce glycated hemoglobin (HbA1C), a measure of average blood sugar.
• Chronic fatigue syndrome (CFS).
• Constipation.
• Depression.
• Fluid retention.
• Headaches.
• Heart conditions.
• Kidney and bladder stones.
• Low blood pressure (hypotension).
• Mental and physical tiredness (fatigue).
• Urinary tract infections (UTIs).
• Other conditions.

More evidence is needed to rate the effectiveness of yerba mate for these uses.

Yerba mate weight loss

Yerba Mate leaf extracts contain components such as chlorogenic acid (monocaffeoylquinic and dicaffeoylquinic acids), hydroxycinnamic acids (caffeic acid, quinic acid) and numerous triterpenic saponins ⁷²⁾. Chlorogenic acid is one of the most abundant polyphenols in fruits such as plums, apples and cherries and has been shown to reduce body weight as well as improve lipid metabolism and levels of obesity-related hormones in mice ⁷³⁾. Chlorogenic acid inhibits adipogenesis by reducing the expression of genes regulating adipogenesis in 3T3-L1 cells and in mouse model of high fat diet-induced obesity ⁷⁴⁾. The mechanisms of Yerba Mate on fat decrease, while not directly known, might be due to effects of single components, as investigated in previous studies.

Yerba Mate suppresses body weight gain and visceral fat accumulation and decreases serum levels of cholesterol, triglycerides, LDL cholesterol ⁷⁵⁾. Previous study ⁷⁶⁾ reported that Yerba Mate reduces body weight in mice with obesity induced by a high-fat diet. After feeding animals Yerba Mate for 4 weeks, we observed a decrease in total cholesterol, leptin levels and blood glucose that ultimately led to reduce their body weight ⁷⁷⁾. Taking into account that Yerba Mate is especially rich in chlorogenic acid and several bioactive compounds, it suggest that it is possible to inhibit obesity.

In a 12 weeks, randomized, double-blind, placebo-controlled clinical trial involving 30 obese Korean people who met the study criteria (age, 43.2 ± 10.6 years; weight, 71.56 ± 10.14 kg; BMI 27.98 ± 2.68 kg/m²) were randomly divided into two groups (n = 15 each) and given either Yerba Mate (3150 mg/day) or a placebo (3150 mg/day) ⁷⁸⁾. The Yerba Mate was a standardized product containing chlorogenic acid 35 mg/g and was prepared by Jeju, Republic of Korea. Dried Yerba Mate leaves were collected from Argentina and extracted with water at 100 °C for 2 h. Extracts were filtered and concentrated under reduced pressure to 20 brix at 40–50 °C, dried at 160–180 °C using a spray dryer. Yerba Mate was administered in capsule form (333.38 mg Yerba Mate and 16.6 mg diluting agents in a 350 mg capsule). Administration was 3 g/day Yerba Mate water extract, the recommended daily dose from Korea Food & Drug Administration (KFDA) in that clinical trial. The appearance of the Yerba Mate and placebo capsules was identical. The Yerba Mate used in this study contained 35 mg/g chlorogenic acid. Yerba Mate extracts are especially rich in chlorogenic acids that might contribute to hypocholesterolemic ⁷⁹⁾ and weight loss effects ⁸⁰⁾.

Subjects take three capsules per each meal, total three times in a day (before breakfast, lunch and dinner). Yerba Mate and placebo capsule packaging was indistinguishable and was labeled with the subject number. Subjects were instructed to bring all remaining supplements to each visit and were withdrawn if supplement consumption was < 70 % of the recommended dose.

After 12 weeks of supplementation, the research authors observed a significant decreased in body fat mass and percent body fat. Waist hip ratio also decreased significantly in the Yerba Mate group compared to the placebo group. Unlike currently prescribed anti-obesity drugs, subjects did not report any specific adverse events. Results of subjects’ complete blood cell count, liver and kidney function tests and vital signs were within normal ranges for both the Yerba Mate and placebo groups throughout the study. Suggesting that Yerba Mate supplementation did not cause any adverse side effects ⁸¹⁾.

This clinical study ⁸²⁾ was the first controlled trial ascribing an anti-obesity effect to the ingestion of yerba mate herb. Yerba Mate was previously tested in a supplement with other ingredients such as green tea, asparagus, black tea, guarana and kidney bean extracts ⁸³⁾. Another clinical trial of 6 weeks of treatment with green yerba mate powder extract (1200 mg/day) showed significant decreased in body fat mass and percent body fat ⁸⁴⁾.

Previous animal study showing that adipocyte size decreased in a group given Yerba Mate ⁸⁵⁾. Yerba Mate decreases the differentiation of preadipocytes and reduces accumulation of lipids in adipocytes ⁸⁶⁾. Additionally, Yerba Mate inhibits body weight gain and visceral fat accumulation and decreases serum levels of cholesterol, triglycerides, LDL cholesterol ⁸⁷⁾. These results indicate that decreasing adipose tissue growth, body fat mass (kg), percent body fat (%) and obesity of Yerba Mate. The potential thermogenic properties of significantly increasing resting energy expenditure for at least four hours post-ingestion in moderated-level habitual caffeine consumers ⁸⁸⁾. The increase in resting energy expenditure might have been due to a 340-mg proprietary blend of caffeine anhydrous, guarana, yerba mate and green tea extract. Another study evaluated the acute effects of oral administration of 12 commercially available plant preparations aimed at treating human obesity. Only treatment with a green Yerba mate extract changed the respiratory quotient, indicating a rise in the proportion of oxidized fat that might have led to decreased body fat. These results suggest the potential of mate leaves for treatment of obesity ⁸⁹⁾.

The study author concluded by stating that the study is an exploratory clinical trial using standardized Yerba Mate and the study is insufficient to show the effects of Yerba Mate when associated with lifestyle modification. For full determination of the long-term effects of Yerba Mate clinical application, a larger sample size is needed.

Yerba mate side effects

Yerba mate is possibly safe for most people, when taken by mouth for short periods of time. Yerba mate contains caffeine, which in some people can cause side effects such as inability to sleep (insomnia), nervousness and restlessness, upset stomach, nausea and vomiting, increased heart rate and breathing, high blood pressure, headache, ringing in the ears, irregular heartbeats, and other side effects.

Yerba mate is possibly UNSAFE when taken in large amounts or for long periods of time. It increases the risk of esophageal cancer, kidney cancer, stomach cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, and possibly laryngeal or mouth cancer. This risk is especially high for people who smoke or drink alcohol.

Yerba mate is likely UNSAFE when taken in very large amounts, due to its caffeine content.

Special precautions and warnings

Yerba mate and cancers

It is believed that consumption of Yerba mate is associated with increased risk of oral cancer ⁹⁰⁾, esophageal cancer ⁹¹⁾, cancer of the larynx ⁹²⁾ and squamous cell cancers of the head and neck ⁹³⁾, but the carcinogenic mechanism is unclear ⁹⁴⁾, ⁹⁵⁾. Commercial brands of Yerba mate contain high levels of carcinogenic polycyclic aromatic hydrocarbons, which are acquired during the traditional drying process. Some authors believe that it’s the very hot (> 65 °C) Yerba mate beverages is probably associated with increased risk of oesophageal cancer ⁹⁶⁾, ⁹⁷⁾, whilst others believe it’s the high levels of carcinogenic polycyclic aromatic hydrocarbons from drinking Yerba mate ⁹⁸⁾ as measured from increased urinary concentrations of some polycyclic aromatic hydrocarbon metabolites in Yerba mate drinkers which is as much as smoking cigarettes. While it is true that the temperature of hot infusions may influence the risk of esophageal squamous cell carcinoma ⁹⁹⁾, ¹⁰⁰⁾, ¹⁰¹⁾, the polycyclic aromatic hydrocarbon content in Yerba mate is not affected by the water temperature ¹⁰²⁾. These results confirm that drinking yerba mate is a source of exposure to potentially carcinogenic polycyclic aromatic hydrocarbons, consistent with the hypothesis that the polycyclic aromatic hydrocarbon content of maté may contribute to the increased risk of esophageal squamous cell carcinoma in Yerba mate drinkers.

While the epidemiological data indicate that Yerba mate users have an increased risk of oral and oro-pharyngeal cancer, little is known about whether this increased risk is due to the high temperature of the beverage when it is consumed or due to certain carcinogenic constituents that are present in Yerba mate. More human and animal studies are needed before a conclusion can be made on the oral and oro-pharyngeal carcinogenic risk of Yerba mate to humans.

Children: Yerba mate is possibly UNSAFE for children when taken by mouth. Yerba mate is linked with an increased risk of esophageal cancer, kidney cancer, stomach cancer, bladder cancer, cervical cancer, prostate cancer, lung cancer, and possibly laryngeal or mouth cancer.

Pregnancy and breast-feeding: Yerba mate is possibly UNSAFE when taken by mouth during pregnancy. One concern is that using yerba mate seems to increase the risk of getting cancer. It’s not known whether that risk is transferred to the developing fetus. Another concern is the caffeine content of yerba mate. Caffeine crosses the placenta and enters the fetus’ bloodstream, producing caffeine levels in the fetus that resemble the caffeine level in the mother. In general, mothers should avoid consuming more than 300 mg of caffeine daily; that’s about 3 cups of coffee or tea. Infants born to mothers who consume a lot of caffeine during pregnancy sometimes show symptoms of caffeine withdrawal after birth. High doses of caffeine have also been linked with miscarriage, premature delivery, and low birth weight. However, researchers studied mothers who drank yerba mate tea during pregnancy and found no strong link between drinking yerba mate and premature delivery or small birth weight. But this study has been criticized because it did not consider the amount of yerba mate or caffeine used by the mothers; it looked only at how often they used yerba mate.

Yerba mate is also possibly UNSAFE during breast-feeding. It is not known whether the cancer-causing chemicals in yerba mate pass into breast milk, but that is a concern. The caffeine in yerba mate is also a problem. It might cause irritability and increased bowel movements in nursing infants.

Alcoholism: Heavy alcohol use combined with long-term yerba mate use increases the risk of cancer from 3-fold to 7-fold.

Anxiety disorders: The caffeine in yerba mate might make anxiety disorders worse.

Bleeding disorders: Caffeine might slow clotting. As a result, there is a concern that the caffeine in yerba mate might make bleeding disorders worse. But so far, this effect has not been reported in people.

Heart conditions: Caffeine in yerba mate can cause irregular heartbeats in certain people. If you have a heart condition, discuss using yerba mate with your healthcare provider.

Diabetes: Some research shows that the caffeine in yerba mate may affect the way people with diabetes process sugar and may complicate blood sugar control. There is also some interesting research that shows caffeine may make the warning symptoms of low blood sugar in people with type 1 diabetes more noticeable. Some studies show that the symptoms of low blood sugar are more intense when they start in the absence of caffeine, but as low blood sugar continues, symptoms are greater with caffeine. This might increase the ability of people with diabetes to detect and treat low blood sugar. However, the downside is that caffeine might actually increase the number of low-sugar episodes. If you have diabetes, talk with your healthcare provider before using yerba mate.

Diarrhea: Yerba mate contains caffeine. The caffeine in yerba mate, especially when taken in large amounts, can worsen diarrhea.

Glaucoma: Using yerba mate increases the pressure inside the eye due to the caffeine it contains. The increase in pressure occurs within 30 minutes and lasts for at least 90 minutes. If you have glaucoma, discuss your use of yerba mate with your healthcare provider.

High blood pressure: The caffeine in yerba mate might increase blood pressure in people with high blood pressure. Consuming 250 mg of caffeine can increase blood pressure in healthy people, but this doesn’t seem to happen in people who use caffeine all the time.

Irritable bowel syndrome (IBS): Yerba mate contains caffeine. The caffeine in yerba mate, especially when taken in large amounts, can worsen diarrhea and might worsen symptoms of IBS.

Weak bones (osteoporosis): Some researchers have found that postmenopausal women who drink a liter or more daily of a traditional South American yerba mate tea have higher bone density. However, the caffeine in yerba mate tends to flush calcium out of the body in the urine. This can contribute to weak bones. For this reason, many experts recommend that caffeine intake be limited to less than 300 mg per day (approximately 2-3 cups of yerba mate). Taking extra calcium may help to make up for the calcium that is flushed out.

There are some women who are at special risk for weak bones. These women have an inherited condition that makes it hard for them to use vitamin D properly. Vitamin D works with calcium to build strong bones. These women should be especially careful to limit the amount of caffeine they get from yerba mate as well as other sources.

Smoking: The risk of getting cancer is 3 to 7 times higher in people who smoke and use yerba mate for long periods of time.

Interactions with medications

Major

Do NOT take this combination.

Amphetamines

Stimulant drugs such as amphetamines speed up the nervous system. By speeding up the nervous system, stimulant medications can make you feel jittery and increase your heart rate. The caffeine in yerba mate might also speed up the nervous system. Taking yerba mate along with stimulant drugs might cause serious problems including increased heart rate and high blood pressure. Avoid taking stimulant drugs along with yerba mate.

Cocaine

Stimulant drugs such as cocaine speed up the nervous system. By speeding up the nervous system, stimulant medications can make you feel jittery and increase your heart rate. The caffeine in yerba mate might also speed up the nervous system. Taking yerba mate along with stimulant drugs might cause serious problems including increased heart rate and high blood pressure. Avoid taking stimulant drugs along with yerba mate.

Ephedrine

Stimulant drugs speed up the nervous system. Caffeine (contained in yerba mate) and ephedrine are both stimulant drugs. Taking caffeine along with ephedrine might cause too much stimulation and sometimes serious side effects and heart problems. Do not take caffeine-containing products and ephedrine at the same time.

Moderate

Be cautious with this combination

Adenosine (Adenocard)

Yerba mate contains caffeine. The caffeine in yerba mate might block the effects of adenosine (Adenocard). Adenosine (Adenocard) is often used by doctors to do a test on the heart. This test is called a cardiac stress test. Stop consuming yerba mate or other caffeine-containing products at least 24 hours before a cardiac stress test.

Antibiotics (Quinolone antibiotics)

The body breaks down caffeine to get rid of it. Some antibiotics might decrease how quickly the body breaks down caffeine. Taking these antibiotics along with yerba mate can increase the risk of side effects including jitteriness, headache, increased heart rate, and other side effects.

Some antibiotics that decrease how quickly the body breaks down caffeine include ciprofloxacin (Cipro), enoxacin (Penetrex), gatifloxacin (Tequin), levofloxacin (Levaquin), lomefloxacin (Maxaquin), moxifloxacin (Avelox), norfloxacin (Noroxin), ofloxacin (Floxin), sparfloxacin (Zagam), and trovafloxacin (Trovan).

Carbamazepine (Tegretol)

Carbamazepine is a drug used to treat seizures. Caffeine can decrease the effects of carbamazepine. Since yerba mate contains caffeine, in theory taking yerba mate with carbamazepine might decrease the effects of carbamazepine and increase the risk of seizures in some people.

Cimetidine (Tagamet)

Yerba mate contains caffeine. The body breaks down caffeine to get rid of it. Cimetidine (Tagamet) can decrease how quickly your body breaks down caffeine. Taking cimetidine (Tagamet) along with yerba mate might increase the chance of caffeine side effects including jitteriness, headache, fast heartbeat, and others.

Clozapine (Clozaril)

The body breaks down clozapine (Clozaril) to get rid of it. The caffeine in yerba mate seems to decrease how quickly the body breaks down clozapine (Clozaril). Taking yerba mate along with clozapine (Clozaril) can increase the effects and side effects of clozapine (Clozaril).

Dipyridamole (Persantine)

Yerba mate contains caffeine. The caffeine in yerba mate might block the effects of dipyridamole (Persantine). Dipyridamole (Persantine) is often used by doctors to do a test on the heart. This test is called a cardiac stress test. Stop consuming yerba mate or other caffeine-containing products at least 24 hours before a cardiac stress test.

Disulfiram (Antabuse)

The body breaks down caffeine to get rid of it. Disulfiram (Antabuse) can decrease how quickly the body gets rid of caffeine. Taking yerba mate (which contains caffeine) along with disulfiram (Antabuse) might increase the effects and side effects of caffeine including jitteriness, hyperactivity, irritability, and others.

Estrogens

The body breaks down caffeine (contained in yerba mate) to get rid of it. Estrogens can decrease how quickly the body breaks down caffeine. Decreasing the breakdown of caffeine can cause jitteriness, headache, fast heartbeat, and other side effects. If you take estrogens, limit your caffeine intake.

Some estrogen pills include conjugated equine estrogens (Premarin), ethinyl estradiol, estradiol, and others.

Ethosuximide

Ethosuximide is a drug used to treat seizures. Caffeine in yerba mate can decrease the effects of ethosuximide. Taking yerba mate with ethosuximide might decrease the effects of ethosuximide and increase the risk of seizures in some people.

Felbamate

Felbamate is a drug used to treat seizures. Caffeine in yerba mate might decrease the effects of felbamate. Taking yerba mate with felbamate might decrease the effects of felbamate and increase the risk of seizures in some people.

Flutamide (Eulexin)

The body breaks down flutamide (Eulexin) to get rid of it. Caffeine in yerba mate might decrease how quickly the body gets rid of flutamide. This could cause flutamide to stay in the body too long and increase the risk of side effects.

Fluvoxamine (Luvox)

The body breaks down the caffeine in yerba mate to get rid of it. Fluvoxamine (Luvox) can decrease how quickly the body breaks down caffeine. Taking yerba mate along with fluvoxamine (Luvox) might cause too much caffeine in the body, and increase the effects and side effects of yerba mate.

Lithium

Your body naturally gets rid of lithium. The caffeine in yerba mate can increase how quickly your body gets rid of lithium. If you take products that contain caffeine and you take lithium, stop taking caffeine products slowly. Stopping yerba mate too quickly can increase the side effects of lithium.

Medications for asthma (Beta-adrenergic agonists)

Yerba mate contains caffeine. Caffeine can stimulate the heart. Some medications for asthma can also stimulate the heart. Taking caffeine with some medications for asthma might cause too much stimulation and cause heart problems.

Some medications for asthma include albuterol (Proventil, Ventolin, Volmax), metaproterenol (Alupent), terbutaline (Bricanyl, Brethine), isoproterenol (Isuprel), and others.

Medications for depression (MAOIs)

The caffeine in yerba mate can stimulate the body. Some medications used for depression can also stimulate the body. Drinking yerba mate and taking some medications for depression might cause too much stimulation to the body and serious side effects including fast heartbeat, high blood pressure, nervousness, and others could occur.

Some of these medications used for depression include rasagiline (Azilect), selegiline (Eldepryl, Zelapar), tranylcypromine (Parnate), phenelzine (Nardil), and others.

Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs)

Yerba mate contains caffeine. Caffeine might slow blood clotting. Taking yerba mate along with medications that also slow clotting might increase the chances of bruising and bleeding.

Some medications that slow blood clotting include aspirin, clopidogrel (Plavix), diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, warfarin (Coumadin), and others.

Nicotine

Stimulant drugs such as nicotine speed up the nervous system. By speeding up the nervous system, stimulant medications can make you feel jittery and increase your heart rate. The caffeine in yerba mate might also speed up the nervous system. Taking yerba mate along with stimulant drugs might cause serious problems including increased heart rate and high blood pressure. Avoid taking stimulant drugs along with yerba mate.

Pentobarbital (Nembutal)

The stimulant effects of the caffeine in yerba mate can block the sleep-producing effects of pentobarbital.

Phenobarbital

Phenobarbital is a drug used to treat seizures. Caffeine in yerba mate might decrease the effects of phenobarbital and increase the risk of seizures in some people.

Phenylpropanolamine

Yerba mate contains caffeine. Caffeine can stimulate the body. Phenylpropanolamine can also stimulate the body. Taking yerba mate and phenylpropanolamine together might cause too much stimulation and increase heartbeat and blood pressure and cause nervousness.

Phenytoin

Phenytoin is a drug used to treat seizures. Caffeine in yerba mate can decrease the effects of phenytoin. Taking yerba mate with phenytoin might decrease the effects of phenytoin and increase the risk of seizures in some people.

Riluzole (Rilutek)

The body breaks down riluzole (Rilutek) to get rid of it. Taking yerba mate can decrease how fast the body breaks down riluzole (Rilutek) and increase the effects and side effects of riluzole.

Sedative medications (Benzodiazepines)

Benzodiazepines are drugs that cause sleepiness and drowsiness. The body breaks down benzodiazepines to get rid of them. The caffeine in yerba mate might reduce the breakdown of benzodiazepines. This might increase the effects of benzodiazepines and cause too much sleepiness. Do not drink beer if you are taking benzodiazepines.

Some benzodiazepines include alprazolam (Xanax), clonazepam (Klonopin), diazepam (Valium), lorazepam (Ativan), and others.

Stimulant drugs

Stimulant drugs speed up the nervous system. By speeding up the nervous system, stimulant medications can make you feel jittery and speed up your heartbeat. The caffeine in yerba mate can also speed up the nervous system. Consuming yerba mate along with stimulant drugs might cause serious problems including increased heart rate and high blood pressure. Avoid taking stimulant drugs along with yerba mate.

Some stimulant drugs include diethylpropion (Tenuate), epinephrine, nicotine, cocaine, amphetamines, phentermine (Ionamin), pseudoephedrine (Sudafed), and many others.

Theophylline

Yerba mate contains caffeine. Caffeine works similarly to theophylline. Caffeine can also decrease how quickly the body gets rid of theophylline. Taking yerba mate along with theophylline might increase the effects and side effects of theophylline.

Valproate

Valproate is a drug used to treat seizures. Caffeine in yerba mate might decrease the effects of valproate and increase the risk of seizures in some people.

Verapamil (Calan, Covera, Isoptin, Verelan)

The body breaks down the caffeine in yerba mate to get rid of it. Verapamil (Calan, Covera, Isoptin, Verelan) can decrease how quickly the body gets rid of caffeine. Drinking yerba mate and taking verapamil (Calan, Covera, Isoptin, Verelan) can increase the risk of side effects for caffeine including jitteriness, headache, and an increased heartbeat.

Water pills (Diuretic drugs)

Caffeine can decrease potassium levels. Water pills can also decrease potassium levels. Taking yerba mate along with water pills might increase the risk of decrease potassium too much.

Some “water pills” that can deplete potassium include chlorothiazide (Diuril), chlorthalidone (Thalitone), furosemide (Lasix), hydrochlorothiazide (HCTZ, HydroDiuril, Microzide), and others.

Minor – Be watchful with this combination

Alcohol

The body breaks down the caffeine in yerba mate to get rid of it. Alcohol can decrease how quickly the body breaks down caffeine. Taking yerba mate along with alcohol might cause too much caffeine in the bloodstream and caffeine side effects including jitteriness, headache, and fast heartbeat.

Birth control pills (Contraceptive drugs)

The body breaks down the caffeine in yerba mate to get rid of it. Birth control pills can decrease how quickly the body breaks down caffeine. Taking yerba mate along with birth control pills can cause jitteriness, headache, fast heartbeat, and other side effects.

Some birth control pills include ethinyl estradiol and levonorgestrel (Triphasil), ethinyl estradiol and norethindrone (Ortho-Novum 1/35, Ortho-Novum 7/7/7), and others.

Fluconazole (Diflucan)

Yerba mate contains caffeine. The body breaks down caffeine to get rid of it. Fluconazole (Diflucan) might decrease how quickly the body gets rid of caffeine. This could cause caffeine to stay in the body too long and increase the risk of side effects such as nervousness, anxiety, and insomnia.

Medications for diabetes (Antidiabetes drugs)

Diabetes medications are used to lower blood sugar. Yerba mate contains caffeine. Reports claim that caffeine might increase or decrease blood sugar. Yerba mate might interfere with blood sugar control and decrease the effectiveness of diabetes medications. Monitor your blood sugar closely. The dose of your diabetes medication might need to be changed.

Some medications used for diabetes include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), chlorpropamide (Diabinese), glipizide (Glucotrol), tolbutamide (Orinase), and others.

Medications that change the liver (Cytochrome P450 1A2 (CYP1A2) inhibitors)

Yerba mate contains caffeine. Caffeine is broken down by the liver. Some medications decrease how well the liver breaks down other medications. These medications that change the liver might decrease how fast caffeine in yerba mate is broken down in the body. This might increase the effects and side effects of caffeine in yerba mate. Some medications that change the liver include cimetidine (Tagamet), fluvoxamine, mexiletine, clozapine, theophylline, and others.

Metformin (Glucophage)

Yerba mate contains caffeine. The body breaks down caffeine to get rid of it. Metformin (Glucophage) can decrease how quickly the body breaks down caffeine. Taking yerba mate along with metformin might cause too much caffeine in the body, and increase the effects and side effects of caffeine.

Methoxsalen (Oxsoralen)

Yerba mate contains caffeine. The body breaks down caffeine to get rid of it. Methoxsalen (Oxsoralen) can decrease how quickly the body breaks down caffeine. Taking caffeine along with methoxsalen might cause too much caffeine in the body, and increase the effects and side effects of caffeine.

Mexiletine (Mexitil)

Yerba mate contains caffeine. The body breaks down caffeine to get rid of it. Mexiletine (Mexitil) can decrease how quickly the body breaks down caffeine. Taking Mexiletine (Mexitil) along with yerba mate might increase the caffeine effects and side effects of yerba mate.

Terbinafine (Lamisil)

The body breaks down caffeine (contained in yerba mate) to get rid of it. Terbinafine (Lamisil) can decrease how fast the body gets rid of caffeine and increase the risk of side effects including jitteriness, headache, increased heartbeat, and other effects.

Tiagabine

Yerba mate contains caffeine. Taking caffeine over a period of time along with tiagabine can increase the amount of tiagabine in the body. This might increase the effects and side effects of tiagabine.

Ticlopidine (Ticlid)

The body breaks down the caffeine in yerba mate to get rid of it. Ticlopidine (Ticlid) can decrease how quickly the body gets rid of caffeine. Taking yerba mate along with ticlopidine might increase the effects and side effects of caffeine, including jitteriness, hyperactivity, irritability, and others

Interactions with herbs and supplements

Bitter orange

Do not use yerba mate with bitter orange. The combination might overstimulate the body, resulting in increased blood pressure and heart rate, even in people with normal blood pressure.

Calcium

The caffeine in yerba mate tends to increase the body’s elimination of calcium. If you use a lot of yerba mate, ask your healthcare provider if you should take additional calcium to help make up for the calcium that is lost in the urine.

Creatine

There is some concern that combining caffeine, a chemical found in yerba mate, with ephedra and creatine might increase the risk of serious harmful health effects. One athlete who took 6 grams of creatine monohydrate, 400-600 mg of caffeine, 40-60 mg of ephedra, and a variety of other supplements daily for 6 weeks had a stroke. Caffeine might also decrease creatine’s ability to improve athletic performance.

Ephedra (Ma huang)

Don’t use yerba mate with ephedra. This combination can overstimulate the body and increase the risk of serious life-threatening or disabling conditions, such as high blood pressure, heart attack, stroke, and seizures. This combination can also cause death.

Herbs and supplements that contain caffeine

Yerba mate contains caffeine. Using it along with other herbs or supplements that also contain caffeine might increase the risk of caffeine-related side effects. Other natural products that contain caffeine include cocoa, coffee, cola nut, black tea, oolong tea, and guarana.

Herbs and supplements that slow blood clotting

Yerba mate might slow blood clotting. Using it along with other herbs or supplements that have this same effect might increase the risk of bruising and bleeding in some people. Some of these herbs include angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, and others.

Magnesium

Yerba mate contains caffeine. The caffeine in yerba mate might increase how much magnesium is released in the urine.

What is ginkgo biloba

Ginkgo biloba also called Ginkgo, is one of the most ancient seed plant, often referred to as a “living fossil”, because Ginkgo species from as early as the Jurassic Period 170 million years ago have been identified ¹⁾. The sole surviving member of the Ginkgoaceae family, Ginkgo biloba, is a highly adaptable and hardy tree that is dioecious, having separate male and female plants. Some specimens are over 1,000 years old ²⁾. Ginkgo trees begin reproducing after approximately 20 years of maturation, at which time the female produces fruit that is distinctly malodorous ³⁾. The unique, bilobed leaves of Ginkgo biloba are fan-shaped and are similar in appearance to those of the maidenhair fern, giving rise to the common name “maidenhair tree” ⁴⁾. This large tree may live over 1000 years and reach 40 m of height. Originally native to China, Ginkgo biloba is now cultivated worldwide. The attractive appearance of ginkgo trees and their robust nature have lead to widespread cultivation of Ginkgo biloba as an ornamental plant, expanding its range from its origins in China to every country in the temperate zone ⁵⁾. In addition to its horticultural popularity, various parts of the Ginkgo biloba plant have been used for food or medicine. Ginkgo seeds are regularly consumed in Japan, Korea, and China, despite the fact that poisoning, manifesting as gastrointestinal distress, irritability, and tonic or clonic seizures, can result from overconsumption of seeds due to their high 4′-O-methylpyridoxine content ⁶⁾.

Extract from Ginkgo biloba leaves has been used in traditional Chinese medicine for centuries to treat circulatory disorders, asthma, tinnitus, vertigo, and cognitive problems ⁷⁾. Today, Ginkgo biloba extracts are one of the most commonly taken phytomedicines globally ⁸⁾ and are often prescribed in Europe as a nootropic agent (cognitive enhancer) in old age and dementia ⁹⁾. Ginkgo biloba extract contains mainly terpene trilactones, flavonol glycosides, biflavones, alkylphenols, phenolic acids, polyprenols and proanthocyanidins ¹⁰⁾. The most prevalent of these groups are the flavonol glycosides (quercetin, catechin) ¹¹⁾. The terpenoids include ginkgolides and bilobalides, which represent unique components of Ginkgo biloba. Terpene trilactones, flavonol glycosides and proanthocyanidins are thought to be responsible for the pharmacological properties of Ginkgo biloba ¹²⁾, whereas, ginkgolic acids are typically regarded as causing negative biological activities (e.g., cytotoxicity, mutagenicity) ¹³⁾.

Ginkgotoxin, or 4′-O-methylpyridoxine, is also associated with toxicity, but is found primarily in Ginkgo biloba seeds and only in lesser amounts in the Ginkgo biloba leaves and extracts prepared from the leaves ¹⁴⁾. In recent years, the use of fingerprinting to quantify key chemical constituents of plant-based formulations has been advocated as a quality control measure to ensure appropriate quantities of the biologically-active constituents and a lack of ginkgolic acids ¹⁵⁾.

Figure 1. Ginkgo biloba

Ginkgo biloba is commonly available as a oral tablets, capsules or teas, but may also be available in liquid extracts. Ginkgo biloba extract is typically taken orally. Don’t eat raw or roasted Ginkgo biloba seeds, which can be poisonous.

Ginkgo extract is made from the leaves of the Ginkgo biloba tree. The Ginkgo biloba leaves contain a complex mixture of components. The exact formulation of Ginkgo biloba extract in products available to consumers in the U.S. can vary from manufacturer to manufacturer. Ginkgo is marketed in the U.S. as a dietary supplement and the FDA regulations for dietary supplements are different from regulations for prescription or over-the-counter drugs. Federal law does not require dietary supplements to go through the same standards of premarket testing for safety or efficacy as drugs intended to treat, cure, prevent, diagnose, or mitigate disease. In contrast, in Germany and France, Ginkgo biloba extract is regulated as a prescription drug and therefore, requires registration and adherence to specified content standards. The German Commission E (the German equivalent to the U.S. Food and Drug Administration [FDA]), which evaluated the efficacy and safety of herbals licensed for prescription in Germany, approved the monograph on Ginkgo biloba extract specifying contents of 22% to 27% flavone glycosides, 5% to 7% terpene lactones (2.8% to 3.4% ginkgolides A, B, C and 2.6% to 3.2% bilobalide), and not more than 5 ppm ginkgolic acids, due to their cytotoxic and allergenic potential ¹⁶⁾. However, Ginkgo biloba products on the marketplace in the United States and elsewhere exhibit a wide range of component concentrations ¹⁷⁾.

In the U.S., people take Ginkgo biloba for a wide variety of health reasons, mostly to improve brain function and memory. However, clinical trials designed to assess the efficacy of Ginkgo biloba extract have not produced consistent evidence of benefit.

On the basis of animal studies, several mechanisms have been proposed to explain the pharmacological properties of this plant: extract from Ginkgo biloba leaves inhibits platelet-activating factor ¹⁸⁾ and enhances nitric oxide (NO) production in vessels, with subsequent effect on peripheral and cerebral blood flow ¹⁹⁾. Ginkgo biloba extract is thought to modulate different neurotransmitter systems: it is a strong inhibitor of monoamine oxidase A (MOA) and synaptosomal uptake of DA (dopamine), 5-HT (serotonin) and norepinephrine ²⁰⁾. Additionally, Ginkgo biloba displays a free radical scavenger activity and has neuroprotective and antiapoptotic properties, such as inhibition of amyloid-β neurotoxicity and protection against hypoxic challenges and increased oxidative stress ²¹⁾.

The effect of Ginkgo biloba has been studied in a variety of neuropsychiatric conditions. However, the general lack of evidence prevents drawing conclusions regarding Ginkgo biloba effectiveness in many neuropsychiatric conditions, such as autism, ADHD, addiction, generalized anxiety disorder, and tardive dyskinesia ²²⁾. Of all the psychiatric disorders reviewed, dementia has been the most extensively studied. A recent meta-analysis of eight studies in dementia showed that Ginkgo biloba differed significantly from placebo, providing beneficial effects both in cognition and activities of daily living. The results are consistent with another recent 2010 meta-analysis ²³⁾ on the effect of Ginkgo biloba on cognition. On the other hand, the review authors found a significant difference between Ginkgo biloba and placebo for activities of daily living in patients with dementia which were not significant in the aforementioned report ²⁴⁾.

Ginkgo biloba key facts

• There have been a lot of studies on the possible health effects and risks of people using Ginkgo biloba.
• There’s no conclusive evidence that Ginkgo biloba is helpful for any health condition.
• Ginkgo biloba doesn’t help prevent or slow dementia or cognitive decline, according to studies ²⁵⁾, ²⁶⁾, including the long-term Ginkgo Evaluation Memory Study, which enrolled more than 3,000 older adults, ages 75 or older, between 2000 and 2008 ²⁷⁾. Half took ginkgo, half did not. All participants in the Ginkgo Evaluation of Memory (GEM) study took tests of their thinking abilities. The researchers found that 120 milligrams Ginkgo biloba taken twice daily was not effective in reducing the incidence of dementia, lessening cognitive decline, reducing blood pressure or hypertension, or reducing cardiovascular disease events ²⁸⁾.
• There’s no strong evidence that ginkgo helps with memory enhancement in healthy people ²⁹⁾, ³⁰⁾, blood pressure ³¹⁾, intermittent claudication ³²⁾, tinnitus ³³⁾, age-related macular degeneration ³⁴⁾, the risk of having a heart attack or stroke ³⁵⁾ or with other conditions.
• Ongoing research is looking at whether a compound in Ginkgo biloba may help with diabetes.

Research on ginkgo use for specific conditions shows:

• Dementia. There isn’t enough evidence to support the use of ginkgo to prevent dementia or treat people with mild cognitive impairment.
• Claudication. A review of the research suggests that taking ginkgo has no significant benefits for people with this condition.

Ginkgo’s effect on memory enhancement has had conflicting results. While some evidence suggests that ginkgo extract might modestly improve memory in healthy adults, most studies indicate that ginkgo doesn’t improve memory, attention or brain function.

While ginkgo appears to be safe in moderate amounts, research doesn’t support use of the supplement to prevent or slow dementia or cognitive decline. Further research is needed to find out what role ginkgo might play in supporting brain function and treating other conditions.

Can Ginkgo biloba prevent memory loss and improve cognitive function?

Ginkgo biloba extract, derived from the leaves of the Ginkgo biloba tree, is often touted as a memory aid. But it appears unlikely that Ginkgo biloba extract can slow or prevent age-related memory problems, or memory loss associated with mild cognitive impairment or Alzheimer’s disease. Several small, early studies showed modest improvements in cognitive function for older adults with dementia. However, a number of larger studies haven’t confirmed that Ginkgo biloba extract prevents memory loss or slows the progression of cognitive decline or Alzheimer’s disease in older adults. In adults with normal cognition or mild cognitive impairment, Ginkgo biloba does not slow cognitive decline.

Although some studies have shown slight improvements in cognitive function for people taking Ginkgo biloba, most experts feel that Ginkgo biloba hasn’t lived up to its early promise and don’t recommend its use as a memory aid.

Should I stop or start taking Ginkgo biloba extract?

Consumers should be aware that studies have not consistently demonstrated that ginkgo improves brain function. The new National Toxicology Program ³⁶⁾ findings showing that both rats and mice develop cancer after long-term use should also be taken into consideration. Additionally, ginkgo has been shown to interact with other drugs, which can increase or decrease their effects. It is always important to give your health care provider a full picture of what you do to manage your health, including taking dietary supplements. This will help ensure coordinated and safe care.

What do scientists know about Ginkgo biloba safety?

• For many healthy adults, ginkgo appears to be safe when taken by mouth in moderate amounts.
• Side effects of ginkgo may include headache, stomach upset, and allergic skin reactions. If you’re older, have a known bleeding risk, or are pregnant you should be cautious about ginkgo possibly increasing your risk of bleeding.
• In a 2012 research study ³⁷⁾, rodents given ginkgo had an increased risk of developing liver and thyroid cancer at the end of the 2-year tests.
• Ginkgo may interact with some conventional medications, including anticoagulants (blood thinners), research reviews show.
• Eating fresh (raw) or roasted ginkgo seeds can be poisonous and have serious side effects.

Ginkgo biloba extract

The two mechanisms of action most often associated with the proclaimed health benefits of Ginkgo biloba extract are the antagonism of Platelet Activating Factor
(PAF) by the ginkgolides and the antioxidant action of the flavonoids ³⁸⁾. However, there are multiple mechanisms of action that are likely to impact disease pathways. Several mechanisms of action identified through in vitro or in vivo studies are hypothesized to play a role in the health promoting action of Ginkgo biloba extract. These include: antagonism of Platelet Activating Factor by the ginkgolides ³⁹⁾; antioxidant activity of the flavonoids attributed to scavenging of reactive oxygen species, chelation of metal ions, and increasing the concentration of superoxide dismutase and glutathione-S-transferase ⁴⁰⁾; antagonism of major inhibitory receptors of the central nervous system, glycine, and GABA receptors ⁴¹⁾; modulation of neurotransmitter concentrations or receptor densities ⁴²⁾; reduction of nitric oxide release ⁴³⁾; inhibition of mitochondrial dysfunction ⁴⁴⁾; and modulation of P450 enzymes ⁴⁵⁾.

Figure 2. Ginkgo biloba extract bioactive compounds

Ginkgo biloba absorption, distribution, metabolism and excretion

Due to the complex nature of Ginkgo biloba extract with its many structurally diverse constituents, its precise pharmacokinetic profile remains undetermined. However, there have been many pharmacokinetics studies in humans and experimental animals that focus on key chemical classes such as the terpene trilactones
and select flavonol glycosides. In general, Ginkgo biloba extract is well absorbed in humans, rats, and rabbits after oral administration ⁴⁶⁾.

Ginkgo biloba uses

The therapeutic effect most frequently ascribed to Ginkgo biloba use in popular culture is improvement of memory and brain function, however, there are numerous other health benefits attributed to its use. In Germany, Ginkgo biloba is indicated for the treatment of intermittent claudication, decreased mental function (including forgetfulness, early dementia, and concentration problems), and tinnitus ⁴⁷⁾. Ginkgo biloba extract has been studied in humans as treatment for the neurological effects associated with Alzheimer’s disease, traumatic brain injury, stroke, dementia, normal aging, edema, tinnitus, and macular degeneration ⁴⁸⁾. Additionally, preclinical in vitro or experimental animal studies have explored the use of Ginkgo biloba for cardiovascular indications (thrombosis, embolism), anxiety/stress, sexual dysfunction, and cancer ⁴⁹⁾. Despite the popular use of Ginkgo biloba extract for numerous ailments, the largest clinical trial of Ginkgo biloba effects (Ginkgo Evaluation of Memory Study) failed to find an effect of Ginkgo biloba
on prevention of dementia ⁵⁰⁾, prevention of cognitive decline ⁵¹⁾, reduction in cardiovascular disease-related events or mortality ⁵²⁾, or decreases in blood pressure or hypertension ⁵³⁾.

In the largest clinical trial of Ginkgo biloba to date, the Ginkgo Evaluation of Memory (GEM) study ⁵⁴⁾, the researchers looked at data on more than 3,000 people, ages 75 or older, between 2000 and 2008. Half took ginkgo, half did not. All participants in the Ginkgo Evaluation of Memory (GEM) study took tests of their thinking abilities. The researchers found that 120 milligrams Ginkgo biloba taken twice daily was not effective in reducing the incidence of dementia, lessening cognitive decline, reducing blood pressure or hypertension, or reducing cardiovascular disease events ⁵⁵⁾.

Ginkgo biloba dosage

Diamond et al. ⁵⁶⁾ reviewed the literature on the effectiveness of Ginkgo biloba extract and concluded
that positive effects on various endpoints were observed with dosages of 120 to 300 mg per day administered for a period of 3 to 12 weeks. Standardized Ginkgo biloba extract is typically taken in tablet or capsule form at doses in the range of 120 to 240 mg per day. In addition to the standardized extract, Ginkgo biloba is also available as a mother tincture (ethanol extraction of fresh leaves) and as dry leaves for use in tea ⁵⁷⁾.

Ginkgo biloba side effects

When used orally in moderate amounts, Ginkgo biloba appears to be safe for most healthy adults.

Ginkgo biloba can cause:

• Headache
• Dizziness
• Heart palpitations
• Upset stomach
• Constipation
• Allergic skin reactions

Don’t eat raw or roasted Ginkgo biloba seeds, which can be poisonous.

If you are epileptic or prone to seizures, avoid ginkgo. Large amounts of ginkgotoxin can cause seizures. Ginkgotoxin is found in Ginkgo biloba seeds and to a lesser extent, Ginkgo biloba leaves.

If you are older, have a bleeding disorder or are pregnant, don’t take Ginkgo biloba. The supplement might increase your risk of bleeding. If you’re planning to have surgery, stop taking Ginkgo biloba two weeks beforehand.

Ginkgo biloba might interfere with the management of diabetes. If you take ginkgo and have diabetes, closely monitor your blood sugar levels.

Bent et al. ⁵⁸⁾ assessed case reports and concluded a risk of spontaneous bleeding could be associated with Ginkgo biloba use. Kellermann and Kloft ⁵⁹⁾ found 21 reported cases of spontaneous bleeding associated with Ginkgo biloba extract through 2007, with one third of the cases involving concurrent use of antiplatelet or anticoagulant therapies. The hypothesized mechanism of toxicity is that antagonism of Platelet Activating Factor
(PAF) and collagen lead to inhibition of platelet aggregation ⁶⁰⁾. Kellermann and Kloft ⁶¹⁾ conducted a systematic review and meta-analysis that did not find evidence of higher bleeding risk associated with Ginkgo biloba extract therapy. In isolated cases, ginkgo use was associated with  increased blood pressure when combined with thiazide diuretics and coma when combined with trazodone ⁶²⁾. Seizures occurred in two previously well-controlled epileptics within 2 weeks of beginning Ginkgo biloba extract supplementation and resolved after stopping supplementation ⁶³⁾.

The ginkgolic acids present in the ginkgo plant are known to cause contact dermatitis in a manner similar to that elicited by urushiols in poison ivy with limited evidence of cross-reactivity between poison ivy and ginkgo ⁶⁴⁾. For this reason, in Germany, ginkgolic acids are restricted to less than 5 ppm in standardized preparations. Two cases of allergic skin reaction (diffuse mobilliform eruptions and acute generalized excanthematous pustulosis) following oral treatment with Ginkgo biloba products were reported, one in the United States ⁶⁵⁾ and one in Australia ⁶⁶⁾.

Some research has shown that rodents given Ginkgo biloba had an increased risk of developing liver and thyroid cancers

In 2012 the National Toxicology Program ⁶⁷⁾ looked at the long-term effects of Ginkgo biloba extract in mice and rats. Groups of 50 male and female rats received 100, 300, or 1,000 milligrams of Ginkgo biloba extract per kilogram of body weight, and groups of male or female mice received 200, 600, or 2,000 mg/kg each day. Similar groups of animals were given solutions of corn oil with no chemical added and served as the control groups. Ginkgo extract was given orally to the animals for up to 105 weeks. At the end of the two-year studies, tissues from more than 40 sites were examined for every animal. The National Toxicology Program study ⁶⁸⁾ found an increase in liver cancer in male and female mice, and in cancer of the thyroid gland in male and female rats and male mice.

What do the National Toxicology Program studies mean for humans?

The National Toxicology Program ⁶⁹⁾ rodent studies on Ginkgo biloba extract may be relevant to humans. However, these studies represent only the first step in determining if there is a human cancer risk from taking Ginkgo biloba extract as a dietary supplement. The next steps will include identification of components in the extract that may account for the cancer findings, along with the collection of additional information on human consumption of Ginkgo biloba extract.

Interactions with medicines

Possible interactions include:

• Alprazolam (Xanax). Taking Ginkgo biloba with this drug used to relieve symptoms of anxiety might reduce the drug’s effectiveness.
• Anticoagulants and anti-platelet drugs, herbs and supplements. These types of drugs, herbs and supplements reduce blood clotting. Taking Ginkgo biloba with them might increase your risk of bleeding.
• Anticonvulsants and seizure threshold lowering drugs, herbs and supplements. Large amounts of ginkgotoxin can cause seizures. Ginkgotoxin is found in ginkgo seeds and, to a lesser extent, ginkgo leaves. It’s possible that taking Ginkgo biloba could reduce the effectiveness of an anticonvulsant drug.
• Antidepressants. Taking Ginkgo biloba with certain antidepressants, such as fluoxetine (Prozac, Sarafem) and imipramine (Tofranil), might decrease their effectiveness.
• Certain statins. Taking ginkgo with simvastatin (Zocor) might reduce the drug’s effects. Ginkgo also appears to reduce the effects of atorvastatin (Lipitor).
• Diabetes drugs. Ginkgo biloba might alter your response to these drugs.
• Ibuprofen. It’s possible that combining Ginkgo biloba with ibuprofen (Advil, Motrin IB, others) might increase your risk of bleeding.

Toxicity Studies

Experimental animals

The LD50 (lethal dose 50 is where 50% of the test subjects die) of standardized Ginkgo biloba extract administered orally to mice was reported to be 7.73 g/kg
and the LD50 after intravenous administration was 1.1 g/kg for both rats and mice ⁷⁰⁾. There was no evidence of organ damage or impairment of hepatic or renal function when Ginkgo biloba extract was administered orally over 27 weeks to rats and mice at doses ranging from 100 to 1,600 mg/kg ⁷¹⁾. Rats exposed to EGb 761®, which consists of 24% ginkgo-flavone glycosides and 6% terpenoids, at 4, 20, and 100 mg/kg per day for 2 years were reported to show no histopathological changes, however, details of this study are not available ⁷²⁾.

EGb 761®, originated by Dr Willmar Schwabe Pharmaceuticals ⁷³⁾ in the 1990s, is a well-defined mixture of active compounds extracted from Ginkgo biloba leaves according to a standardized procedure. EGb 761® contains approximately 24% flavone glycosides (primarily quercetin, kaempferol and isorhamnetin) and 6% terpene lactones (2.8% to 3.4% ginkgolides A, B and C, and 2.6% to 3.2% bilobalide). Ginkgolide B and bilobalide account for about 0.8% and 3% of the total extract, respectively. Other constituents include proanthocyanidins, glucose, rhamnose, organic acids, D-glucaric and ginkgolic acids. EGb 761 is applied in treating a wide range of disorders, such as hypertension, coronary heart disease, hyperlipidaemia, diabetes, asthma and cancer adjuvant therapy ⁷⁴⁾. There are many laboratory and trial reports focused on the applying of EGb in psychiatric medicine ⁷⁵⁾.

In a chronic study conducted in Fisher 344 rats with quercetin administered by dosed feed at concentrations of 0, 1,000, 10,000, or 40,000 ppm, there were no treatment-related effects on survival, clinical signs, organ weights, or hematological and clinical chemistry parameters ⁷⁶⁾. There were decreases in mean body weights and relative liver and kidney weights in the 40,000 ppm male and female rats.

What is rhodiola rosea

Rhodiola rosea is also known as golden root, Arctic root or rose root, is a succulent herbaceous, perennial flowering plant in the family Crassulaceae ¹⁾. Rhodiola rosea grows naturally in the cooler regions of the world—the Arctic, Scandinavia, North Russia, in the mountains of Asia (the Himalayas, the Altai, and the Ural mountains) and Europe (the Alps, the Pyrenees, the Carpathian Mountains), and in other higher mountainous regions (980 to 2000 m altitude) like those in Bulgaria (the mountains of Sredna Gora, Rila, Pirin, and the Balkan) ²⁾. Rhodiola rosea plant prefers the scree, grassy, or rocky slopes, from mountain to subalpine zone of heights up to 2280 meters altitude ³⁾. Rhodiola rosea is a dioecious plant (having separate male or female plants) with a thick quite branched scaly rhizome (rootstock) with average weight of 70–400 g, but reaching 3.5 kg, too. The Rhodiola rosea root and rhizomes have rose scent. Several shoots grow from the same thick root. The stem is straight, 10–30 cm in height ⁴⁾. The leaves are oblong, elliptic-oblanceolate, or obovate, entire. Inflorescences are corymbiform or capitates, the flowers unisexual, flowers are set from April to August. Propagation is vegetative or by seeds ⁵⁾.

Figure 1. Rhodiola rosea

Historically, people in northern regions have used Rhodiola rosea for anxiety, fatigue, anemia, impotence, infections, headache, and depression related to stress. Traditional folk medicine used Rhodiola rosea to promote work endurance, increase longevity, and to promote resistance to high altitude sickness, fatigue, depression and other health conditions ⁶⁾. Rhodiola rosea may enhance mood and affect via its complex effect on central biogenic amines and β-endorphins. For example, Rhodiola rosea appears to stimulate noradrenalin, serotonin, dopamine, and acetylcholine receptors in brain regions involved in mood and affect ⁷⁾. In in-vitro bioassay studies, Rhodiola rosea has also been shown to inhibit monoamine oxidase A and B enzymes ⁸⁾. Further, studies suggest that Rhodiola rosea may have antidepressant activity via its ability to increase endogenous β-endorphin levels while preventing stress-induced elevation of β-endorphin ⁹⁾ and via its action in prolonging the ‘forced swim test’ in rats ¹⁰⁾. Today, people use Rhodiola rosea as a dietary supplement to increase energy, stamina, and strength, to improve attention and memory, and to enhance the ability to cope with stress. Rhodiola rosea root extracts are also available in capsule or tablet form.

The chemical composition of the extracts from the Rhodiola rosea root and rhizomes was studied by East-European research groups mainly ¹¹⁾. A decade of investigation ¹²⁾ revealed evidences about the presence of different biological active substances in the rhizome of golden root unlike some other Rhodiola species.

Six different groups of chemical components with pharmaceutical interest could be found in the Rhodiola rosea roots and rhizomes: (1) phenylpropanoids—alcohol derivatives of the cinnamon acid and glycosides like rosavin (2.1%) ¹³⁾, rosin and rosarin (which are classified under the general name of “rosavins”) ¹⁴⁾; (2) phenylethanoids—salidroside (rhodioloside) (0.8%), p-tyrosol¹⁵⁾; (3) flavonoids—including rodiolin, rodionin, rodiosin, acetylrodalgin, tricin ¹⁶⁾, and tannins 16–18% ¹⁷⁾; (4) monoterpenes, including rosiridol and rosidarin; (5) triterpenes, such as daucosterol and betasitosterol; (6) phenolic acids such as chlorogenic, hydroxycinnamic, gallic acids ¹⁸⁾ and essential oils ¹⁹⁾. All these substances determine the specificity of the Rhodiola extracts. However, the roots have many other substances like phenolic antioxidant, including proanthocyanidins, quercetin, gallic acid, and chlorogenic acid ²⁰⁾.

Rosavins (rosavin, rosarin, and rosin) and the salidroside or rhodioloside, as well as rodiolin, rodonizid, and roziridine are the most important, and are mainly used as active substances for production of medical preparations. Tyrosol is also a crucial active ingredient; though to a less extent than the other two standards. The rosavins complex is specific for Rhodiola rosea unlike salidroside which presents in other Rhodiola species and in some plants from other genera ²¹⁾.

One of the major results of the research is the detection of differences in the content of biologically active substances in the roots of Rhodiola rosea depending on their habitats ²²⁾. Investigation of Rhodiola rosea root from different Bulgarian mountains areas indicated the highest amount of salidroside of 1.55% in Rila mountain sites, and, respectively, the lowest of 0.72% in Pirin Mountain sites ²³⁾. The stem and the leaves contain less salidroside, while there is no substantial difference in the levels of polyphenols accumulation in the epigeous parts of the plant.

Rhodiola species contain a range of antioxidant compounds, including p-tyrosol, organic acids (gallic acid, caffeic acid, and chlorogenic acid), and flavonoids (catechins and proanthocyanidins) ²⁴⁾. The stimulating and adaptogenic properties of Rhodiola rosea are attributed to p-tyrosol, salidroside (synonym: rhodioloside and rhodosin), rhodioniside, rhodiolin, rosin, rosavin, rosarin, and rosiridin ²⁵⁾. Rosavin is the constituent currently selected for standardization of extracts ²⁶⁾. p-Tyrosol has been shown to be readily and dose-dependently absorbed after an oral dose ²⁷⁾; however, pharmacokinetic data on the other adaptogenic compounds found in Rhodiola rosea is unavailable.

Figure 2. Rhodiola rosea extracts bioactive compounds

[Source ²⁸⁾]

Rhodiola rosea benefits

Rhodiola rosea roots and rhizome extracts are active ingredients in adaptogenic herbal medicinal products and dietary supplements for temporary relief of symptoms of stress, such as fatigue and weakness ²⁹⁾.

There have been some studies of Rhodiola rosea in people; however, the quality of research is limited so firm conclusions about its effectiveness can’t be made.

• Two review articles—published in 2011 ³⁰⁾ and 2012 ³¹⁾ — looked at 15 studies that tested Rhodiola rosea on physical and mental performance in 575 people. Both reviews found evidence that Rhodiola rosea may enhance physical performance and ease mental fatigue, but emphasized that the limited quantity, methodological flaws and quality of available evidence did not allow firm conclusions to be made.
• A small, National Center for Complementary and Integrative Health-supported study ³²⁾ tested Rhodiola rosea against the drug sertraline and a placebo in people with mild-to-moderate major depressive disorder. The patients were given either pharmaceutical grade Rhodiola rosea powdered extract 340 mg (standardized to a content of rosavin 3.07% and rhodioloside 1.95%) or sertraline 50 mg HCl. The 2015 study results showed Rhodiola rosea produced less antidepressant effect versus sertraline in reducing depressive symptoms, but people who took Rhodiola rosea had fewer side effects than those who took sertraline ³³⁾. These findings suggest that Rhodiola rosea, although less effective than sertraline, may possess a more favorable risk to benefit ratio for individuals with mild to moderate depression. However rhodiola’s effectiveness and safety for depression need testing in larger, more powerful studies.

A growing body of evidence has indicated the Rhodiola rosea extract’s potential use in the prevention and treatment of stress and age-related impairments of cognitive functions and mental disorders ³⁴⁾. The stimulating effects of Rhodiola rosea on the CNS (central nervous system) were demonstrated long ago and suggested there were potential benefits on cognitive functions, memory, learning, and attention ³⁵⁾. An active compound, named rhodioloside was isolated and identified as salidroside ³⁶⁾. A pilot study of rhodioloside (syn. salidroside) in 46 healthy human volunteers showed that 2.5 mg salidroside increased attention in cognitive tests 1 hour after a single dose was administered in 83% of subjects, compared with 54% of volunteers who were administered placebo ³⁷⁾. Further studies provided evidence that R. rosea and salidroside exhibit neuroprotective activity ³⁸⁾, suggesting they may be effective in treating neurodegenerative disorders, such as Alzheimer’s disease ³⁹⁾.

Along with salidroside and its aglycone tyrosol (Figure ​2), cinnamyl alcohol, glycosides, and rosavins (collective name of rosavin, rosarin, and rosin) also exhibited stress-protective ⁴⁰⁾, stimulating, and neurotropic activities in rodents; reduced sleep induced by barbital, hexanal, and chloral hydrate in mice ⁴¹⁾; increased locomotor activity in mice ⁴²⁾; and induced anti-depressant-like effects in animal models of depression ⁴³⁾. Salidroside is common for all species of Rhodiola, while phenylpropanoids, rosavin, rosarin, and rosin are specific only for Rhodiola rosea and Rhodiola sachalinensis ⁴⁴⁾. Many publications have reported on the neuroprotective and neurotropic activity of salidroside ⁴⁵⁾; while, there is limited evidence supporting the importance of rosavin, the major active marker ⁴⁶⁾. Rosavin was inactive is rats during a behavioral test of binge eating; while, salidroside dose-dependently reduced or abolished binge eating for the period in which it was elicited ⁴⁷⁾. In another study, salidroside was more effective than rosarin and rosin in inhibiting the expression of IL-1β, and IL-6 in microglial cells, while rosavin was not tested ⁴⁸⁾. Rosavin inhibited the expression of the TNF-related apoptosis-inducing ligand in concanavalin A activated Jurkat T cells, while salidroside was inactive and rosarin had an opposite effect ⁴⁹⁾.

It is unclear which analytical markers are important for assessing the quality and efficacy of Rhodiola rosea herbal preparations intended for treating aging-induced mild cognitive disorders, such as attenuated memory, attention, and learning ability ⁵⁰⁾. Rhodiola rosea preparations are usually standardized for salidroside (1%) and rosavin (3%). The content of active ingredients in herbal preparations depends on many factors, such as the geographic and climate zone it was grown in, which season and under what conditions it was harvested, and how it was dried, extracted, and prepared to give the final dosage form. For example, a high degree of inter-clonal variation was found for all tested constituents (salidroside, tyrosol, rosavin, rosarin, rosin, and cinnamyl alcohol) in six samples of Rhodiola rosea roots collected in various regions of Norway. The highest variation was found for salidroside and tyrosol, showing inter-clonal variations of 92.8 and 87.8%, respectively ⁵¹⁾. Therefore, the preparations obtained by various producers can have quite different active dose levels. Furthermore, the contribution of these active markers to the overall activity of the total extracts was not systematically assessed. It was suggested that these phenolic compounds (rosavin, rosarin, rosin, salidroside/rhodioloside, and tyrosol) have no impact on activity of CYP450 enzymes and do not inhibit CYP3A4, CYP2D6, or CYP1A2 ⁵²⁾. The presence of minor amounts of herbacetin rhamnosides (rhodiosin and rhodionin) may presumably induce inhibition of CYP2D6 ⁵³⁾ in some commercial preparations of Rhodiola rosea ⁵⁴⁾.

It is a challenge to obtain reproducible efficacy and quality of herbal medicinal products, particularly for preparations of the underground parts of Rhodiola rosea ⁵⁵⁾. There may be unpredictable, complex interactions between the active constituents of the Rhodiola rosea extracts that affect the regulation of molecular networks playing an important role in cellular and physiological functions of human organisms ⁵⁶⁾. The pharmacological activity of Rhodiola rosea crude extract is related to many compounds, such as salidroside, tyrosol, rosavin, and other phenolic compounds ⁵⁷⁾. The batch to batch reproducible content of key active markers and the UPLC fingerprint are not a guaranty of reproducible efficacy and safety. Additional bioassays are required to assure reproducible pharmacological activity of herbal medicinal products. These bioassays may serve as validation tools for the quality assurance of complex herbal medicinal products where the total extract contains active pharmaceutical ingredients. In this context, assessment of the correlation between the content of active markers and pharmacological activity of herbal medicinal products is important. Although the dose-response relationship of salidroside and rosavin and dietary supplements was studied ⁵⁸⁾, the correlation between the content and biological activity of various commercial Rhodiola rosea extracts has not been investigated. The standardized content of active markers is necessary for the quality control of herbal preparations containing Rhodiola extracts.

The efficacy of Rhodiola rosea enthanol extract containing 3.1% rosavin, 2.1% salidroside (rhodioloside) and 4.8% rosavins was demonstrated previously on healthy subjects ⁵⁹⁾; subjects experiencing stress and fatigue ⁶⁰⁾ and patients with chronic fatigue ⁶¹⁾ and major depressive disorder ⁶²⁾. In a double blind, placebo-controlled study on 20 healthy subjects, Dimpfel ⁶³⁾ demonstrated that a single dose administration of two capsules containing 200 mg Rhodiola rosea enthanol extract containing 3.1% rosavin, 2.1% salidroside (rhodioloside) and 4.8% rosavins changed the spectral signature of electric brain activity in a stimulating way compared with placebo. The effect was regarded as a safe booster of mental activity during cognitive and emotional challenges. Rhodiola rosea enthanol extract containing 3.7% rosavin, 3.1% salidroside (rhodioloside) and 5.1% rosavins was also studied earlier in isolated skeletal muscle cells ⁶⁴⁾, animals ⁶⁵⁾, and healthy human subjects ⁶⁶⁾. Oral administration of 100 mg/kg of Rhodiola rosea root extract led to significant attenuation of α1, α2, β1, β2, δ, and θ waves of the electropharmacograms, which are associated with the activation of dopamine, serotonin, glutamate, GABA, acetylcholine, and norepinephrine-mediated signaling pathways ⁶⁷⁾. The most affected were α2 (dopaminergic transmission – CNS stimulating effect) and β1 (glutaminergic transmission – CNS stimulating effect) in the frontal cortex. The next strongest changes were seen in the striatum, and the weakest changes in the reticular formation. Spectral changes lasted up to 4 hours after administration. A concentration of Rhodiola rosea extract 5 mg/L induced a slight increase in the amplitude of the population spike and an increase in long-term potentiation. Further increases were observed by increasing the concentration up to 30 mg/L. During theta burst stimulation, amplitudes of more than 4 mV were measured, indicating their effect on long-term potentiation.

A meta-analysis on the putative antidepressant action of Rhodiola extract revealed it was effective on major depressive disorder (146 subjects) and stress-induced mild depression (714 individuals) ⁶⁸⁾. Rosavin was not included in that study. In mice, the treatment for 5 days (12 and 24 mg/kg) with salidroside (rhodioloside) or fluoxetine prevented the development of the depression-like behavior and of the downregulation of brain-derived neurotrophic factor (BDNF) protein levels in the hippocampus induced by a single injection of lipopolysaccharide ⁶⁹⁾.

Rhodiola rosea for physical fatigue

Rhodiola rosea as single ingredient versus placebo

A three arm double blind randomized controlled trial compared the effect of Rhodiola rosea (as a single ingredient) to placebo, or nothing ⁷⁰⁾. The study examined muscle recovery in 30 adults by measuring C-reactive protein (CRP) and creatinine kinase (CK) levels in blood. Subjects underwent an exhausting physical exercise test on day 30 which consisted of cycling at 20 W on a bicycle ergometer with power increased by 10 W/min until volitional exhaustion (i.e. subject could no longer pedal at 60 rpm). Findings indicate that Rhodiola rosea significantly lowered CRP levels at 5 hours and 5 days after the test but that creatinine kinase (CK) levels were not significantly different between groups. Adverse events were not reported.

A double-blind cross-over randomized controlled trial examined the effect of Rhodiola rosea on exercise performance in twelve male subjects ⁷¹⁾. Subjects received Rhodiola rosea or identical placebo for 3 days before outcomes were measured by an exercise test and another dose on the day of the test. A wash-out period of 7 to 14 days separated cross-over to the opposite treatment. The primary outcome was muscle recovery measured by ATP levels and secondary outcomes were time to exhaustion and perceived exertion; all outcomes were measured at baseline, during the exercise test and during recovery. There was no significant difference between groups in Pi, phosphocreatine and ATP levels, time to exhaustion and perceived exhaustion. Adverse events and drop-outs were not mentioned.

Rhodiola rosea plus starch versus starch alone

One cross-over randomized controlled trial and one controlled clinical trial described in a single report examined the acute and long-term effects, respectively, of Rhodiola rosea on exercise performance ⁷²⁾. In both studies, endurance capacity was the primary outcome and muscle strength, speed of limb movement, reaction time and sustained attention were secondary outcomes.

In the first study on acute effects, Rhodiola rosea combined with starch or placebo was taken on each of 2 days ⁷³⁾. One hour after ingestion on each day, outcomes were measured while subjects underwent a physical functioning test. After a five day washout period, subjects switched to the alternate treatment and performed the same tests. Baseline measurements were not taken. Three out of six parameters of endurance capacity (time to exhaustion, O2 uptake and CO2 output) significantly improved in the Rhodiola rosea group. There was no difference between groups in any secondary outcomes. After five days, authors stated that 12 subjects were reassigned to intervention and control groups for the long-term evaluation study. The long term study evaluated subjects receiving same intervention and control as in the acute study twice per day over a four week period ⁷⁴⁾. The same outcomes as in the acute study were measured. Long term supplementation produced no significant difference in any outcomes between treatment groups; one participant on Rhodiola rosea dropped out during long term supplementation for medical reasons unrelated to the study protocol (reason not stated). One subject with strong headaches during acute supplementation and one with minor headaches during long term supplementation were both on placebo. One subject experienced a minor headache and another had insomnia during long term supplementation of Rhodiola rosea. It is unclear why the long-term study was not randomized.

Rhodiola rosea plus cordyceps versus placebo

Two double blind randomized controlled trials conducted evaluate the effect of Rhodiola rosea combined with other herbs on exercise performance ⁷⁵⁾. Both studies were conducted by the same group of authors using slightly different protocols and populations. In both studies, intervention capsules were described as every 3 capsules containing 300 mg of Rhodiola rosea (standardized to 3.0% rosavins and 2.5% salidrosidesminimum), 1000 mg of Cordyceps sinensis, a Chinese herb reported to improve circulation ⁷⁶⁾, and 800 mg of the manufacturers ‘proprietary blend’ of substances (undisclosed).

In one of the randomized controlled trials, 17 male were randomly assigned to either the Rhodiola rosea-containing formulation or placebo for 15 days ⁷⁷⁾. Subjects took six capsules per day for 4 days (loading dose) then three capsules per day 11 days (maintenance dose). Endurance capacity was measured by multiple parameters including peak CO2 output, power output, time to exhaustion and peak heart rate, which were measured at the beginning and end of the study period. The authors found that the herbal formulation did not have any significant effect on exercise endurance or capacity. Adverse events were not reported.

The second study involving eight male cyclists randomized to either Rhodiola rosea-containing formulation (33.0 ± 12.6) years) or placebo (23.8 ± 2.9 years), followed the same protocol as above, however the study period was only 13 days – 6 days of the loading dose and 7 days of the maintenance dose ⁷⁸⁾. Respiratory parameters were measured in the participants. This study also found no significant difference in outcomes between groups. There were no drop outs; adverse events were not mentioned.

Rhodiola rosea for mental fatigue

A double blinded randomized controlled trial assessed the efficacy of a Rhodiola rosea extract, 3.1% rosavin, 2.1% salidroside and 4.8% rosavins, for stress related fatigue ⁷⁹⁾. Sixty subjects were randomized to receive 576 mg of Rhodiola rosea preparation or placebo per day for 28 days. Mental fatigue, measured by the Pines burnout scale, was the primary outcome. Other outcomes evaluated were depression (Montgomery-Asberg Depression Rating Scale, MADRS), quality of life (Medical Outcomes Study Short form 36-item questionnaire, SF-36), attention (Conners’ Computerized Continuous Performance Test II, CCCPT II) and “anti-fatigue” effect (saliva cortisol response after awakening). All outcomes were measured before and after the treatment period. The Pines burnout scale scores and two out of five indices of CCCPT II improved in favour or Rhodiola rosea. While investigators conclude that the treatment appears to have beneficial effect, they report excluding follow-up data for at least 5 participants due to physical loss of data and protocol deviations. Per-protocol analyses (i.e. analysis of only participants who followed the protocol for the entirety of the study) may overestimate treatment effect if the reasons for incomplete data are related to the treatment effect ⁸⁰⁾ – in this case, it is not explicitly stated what “protocol deviations” occurred. No adverse effects occurred during the study period.

Rhodiola rosea for non-specific fatigue was evaluated in a double-blind crossover randomized controlled trial in 56 Armenian physicians ⁸¹⁾. Participants were randomized to either 170 mg Rhodiola rosea (standardized to 2.6% salidroside) or placebo. The study period lasted for two weeks followed by a two-week wash-out period, after which participants were crossed over for two weeks. The primary outcome was fatigue, measured using a fatigue index developed for use in this study; the tool does not appear to be validated. Measurements were carried out before and after the treatment period. Authors ⁸²⁾ state that they found a significant improvement in the fatigue index after two weeks of Rhodiola rosea supplementation, but only present data for the 5 individual test scores. Since we are unable to replicate and confirm their analysis, findings of this study must be interpreted as inconclusive. Authors indicate that no adverse events occurred; whether or not anyone dropped out of the study was not reported.

A double-blinded randomized controlled trial conducted in Russia evaluated the effect of two different single doses of Rhodiola rosea on mental fatigue ⁸³⁾. Subjects were randomized to take Rhodiola rosea or placebo. A non-treatment group was also included, however subjects were not randomized into this group and comparisons against this group will not be considered in this review. The intervention was taken at 4:00 am while participants were on an overnight shift. Capacity for mental work, measured using a fatigue index of unknown origins and pulse pressure and rate were evaluated before night duty and one hour after taking the study medication. A self-report questionnaire evaluating general well-being was completed after taking the study medication. The fatigue index was comprised of three parameters: visual perception, short-term memory and perception of order. Improvements in favour of both doses of Rhodiola rosea were apparent in the fatigue index; no significant differences between groups occurred for other outcomes. The method of randomization was unclear. One subject in the placebo group experienced hypersalivation; whether or drop-outs occurred was not reported.

A double-blinded randomized controlled trial pilot study examined the effect of a repeated low dose of Rhodiola rosea on foreign students’ mental and physical well-being during their examination period ⁸⁴⁾. Subjects were randomized into 2 groups to receive either 100 mg Rhodiola rosea once per day or identical placebo for 20 days. Hand-eye coordination (maze test), motoric speed (tapping test), mental work capacity (correction of text test), fatigue and well-being (self-evaluation questionnaire), heart rate and physical work capacity (bicycle ergometer test) were assessed. Significant improvements were observed in hand-eye coordination, mental fatigue and general-well being in favour of Rhodiola rosea. Students on placebo had a significantly higher heart rate. Drop-outs and adverse events were not reported by authors.

Another randomized controlled trial conducted by the same group examined 60 male students in their first year of study at a Russian high school ⁸⁵⁾. Students were randomized into 3 groups to receive either of Rhodaxon (Rhodiola rosea extract with no ethyl alcohol per day; proportions of active constituents not given), placebo or nothing for 20 days. Participants underwent the same tests for mental and physical capacity as above as well as a psychophysiological test ⁸⁶⁾ to determine level of anxiety, psychological fatigue and need to rest. A comparative analysis between groups was not conducted leaving the effect of Rhodiola rosea indeterminable. Adverse events and drop-outs were not reported.

Rhodiola rosea on endurance exercise performance

The results of this study ⁸⁷⁾ show that acute ingestion of Rhodiola rosea by recreationally fit women can lower the perception of effort during high-intensity endurance exercise and improve performance when the goal is to complete a given distance as quickly as possible. The study authors observed a tendency for the subjects to be able to sustain a higher workload at a heart rate of 170 beats per minute after 20 days of supplementation of 100 mg/day of Rhodiola rosea. Spasov et al. ⁸⁸⁾ also found that heart rate recovered significantly faster after exercise in the Rhodiola rosea group. It is unclear from the present data what caused the reduction in heart rate during the warm-up after Rhodiola rosea treatment. This has obvious implications for recreational athletes, or “weekend warriors,” who may choose to compete in endurance events. However, caution should be used when extrapolating these results to other populations. For example, it is unclear whether similar results would be seen in highly trained endurance athletes who consumed Rhodiola rosea before races. It is also unclear whether the effects seen from an acute dose would be seen with chronic dosing. Because a previous study has shown a loss of effect with chronic treatment ⁸⁹⁾, athletes might want to use Rhodiola rosea sparingly in an attempt to maintain the ergogenic effects. That clinical trial ⁹⁰⁾ also shows that acute ingestion of Rhodiola rosea can lower the heart rate response to submaximal exercise. Although this effect was very pronounced from a statistical standpoint, the real-world benefits of this to athletes who consume Rhodiola rosea before competition or training is currently unknown. It is a common popular belief that Rhodiola rosea can decrease the body’s response to stress, and many athletes consume Rhodiola in the hopes that it can help them deal with a heavy training schedule and the stress of modern life. Although it cannot be ruled out that chronic supplementation may be beneficial in this respect, this study found no evidence that Rhodiola rosea can reduce the activation of the hypothalamic-pituitary-adrenal system’s after intense exercise ⁹¹⁾.

Rhodiola rosea dosage

Dosage varies depending upon standardization. For chronic administration, a daily dose of 360-600 mg Rhodiola extract standardized for 1% rosavin, 180-300 mg of an extract standardized for 2% rosavin, or 100-170 mg of an extract standardized for 3.6% rosavin is suggested. Clinical studies reporting a positive effect of Rhodiola rosea on physical performance reported doses of 100 mg/day ⁹²⁾ and 680 mg/day and those reporting a positive effect on mental fatigue reported doses between 100–576 mg/day ⁹³⁾. For depressive disorder, pharmaceutical grade Rhodiola rosea powdered extract 340 mg/day (standardized to a content of rosavin 3.07% and rhodioloside 1.95%) for 12 weeks ⁹⁴⁾.

Administration is normally begun several weeks prior to a period of expected increased physiological, chemical, or biological stress, and continued throughout the duration of the challenging event or activity.

When using Rhodiola rosea as a single dose for acute purposes (e.g., for an exam or athletic competition), the suggested dose is three times the dose used for chronic supplementation.

Rhodiola rosea has been administered for periods ranging from as little as one day (acute administration) up to four months. Until more specific information is available, a dosing regimen following the established patterns used with other plant adaptogens – with periodic intervals of abstinence – seems warranted when Rhodiola rosea is being used chronically.

Rhodiola rosea side effects

When taken orally (by mouth), Rhodiola rosea may cause dizziness and dry mouth. Clinical feedback indicates, at doses of 1.5-2.0 grams and above, Rhodiola rosea extract standardized for 2% rosavin might cause some individuals to experience an increase in irritability and insomnia within several days.

Out of 446 subjects examined in the 11 included clinical studies ⁹⁵⁾, five adverse events were mentioned in three studies. Two subjects on 200 mg of Rhodiola rosea over a 4-week period each experienced a minor and serious headache ⁹⁶⁾; there appear to be few side effects associated with Rhodiola rosea supplementation; those identified are of a mild nature ⁹⁷⁾.

Evidence on the safety and appropriateness of Rhodiola rosea supplementation during pregnancy and lactation is currently unavailable.

What is capsicum

Capsicum is commonly known as red pepper or chili pepper that is a genus of flowering plants in the nightshade family Solanaceae with approximately 35 species, comprises the well-known sweet and hot chili peppers and several wild species ¹⁾. Capsicum species are native to the tropical and temperate Americas and distributed from Mexico to Brazil, Paraguay and Central Argentina, where they have been cultivated for thousands of years ²⁾. The capsicum genus is of great economic importance because it includes the sweet and hot chili peppers, which are vegetables and spices cultivated and consumed worldwide. The economically most important species belong to the Capsicum annuum complex (Capsicum annuum, Capsicum chinense and Capsicum frutescens); two other species (Capsicum baccatum and Capsicum pubescens) are cultivated predominantly in Latin America ³⁾.

The capsicum fruit (technically berries in the strict botanical sense) plants have a variety of names depending on place and type. The more piquant varieties are commonly called chili peppers, or simply chilis. The large, mild form is called bell pepper, or by color or both (green pepper, green bell pepper, red bell pepper, etc.) in North America and the United Kingdom, but typically called capsicum in New Zealand, Australia, South Africa, Singapore, and India. Capsicum fruits of several varieties with commercial value are called by various European-language names in English, such as jalapeño, peperoncini, and peperoncito; many of these are usually sold pickled. Paprika (in English) refers to a powdered spice made of dried Capsicum of several sorts, though in Hungary and some other countries it is the name of the fruit as well. Both whole and powered chili are frequent ingredients in dishes prepared throughout the world, and characteristic of several cuisine styles, including Mexican, Sichuan (Szechuan) Chinese, Cajun and Creole, along with most South Asian and derived (e.g. Jamaican) curries ⁴⁾. The powdered form is a key ingredient in various commercially prepared foodstuffs, such as pepperoni (a sausage), and chili con carne (a stew), and hot sauces.

Capsicum species are shrubs (annuals in cultivation and as weeds) that produce flowers with mostly stellate to rotate corollas (exceptionally also urceolate or campanulate) that show diverse patterns of pigmentation, and fleshy, mostly globose berries of different sizes and colors (Figures 2 and 3). At the morphological level, Capsicum exhibits an exceptional feature in Solanaceae, which is an entire cup-shaped calyx, mostly with five to ten teeth as nerve prolongations (Figures 2 and 3), shared only with Lycianthes. The two genera differ in two main characters: the anther opening by longitudinal slits and the presence of a nectary in Capsicum, in contrast to the anther opening by apical pores and the absence of a nectary in Lycianthes. Another remarkable feature of Capsicum is the occurrence of dysploidy, as the base chromosome number can be either x = 12 or 13 ⁵⁾. Probably the most singular character in Capsicum is fruit pungency due to the production of capsaicinoids, an exclusive group of alkaloids synthesized in the placenta of the fruits ⁶⁾ and also in the pericarp in ‘super-hot’ chili peppers ⁷⁾. However, non-pungent fruits are produced in some species (e.g. Capsicum rhomboideum, Capsicum geminifolium) and particular cultivars ⁸⁾.

Many varieties of the same species can be used in many different ways; for example, Capsicum annuum includes the “bell pepper” variety, which is sold in both its immature green state and its red, yellow, or orange ripe state. This same species has other varieties, as well, such as the Anaheim chillies often used for stuffing, the dried ancho (also sometimes referred to as poblano) chili used to make chili powder, the mild-to-hot jalapeno, and the smoked, ripe jalapeno, known as chipotle.

Capsicum is also taken by mouth for various problems with digestion including upset stomach, intestinal gas, stomach pain, diarrhea, and cramps. It is also used for conditions of the heart and blood vessels including poor circulation, excessive blood clotting, high cholesterol, and preventing heart disease. Some people use capsicum for burning mouth syndrome, improving exercise performance, irritable bowel syndrome (IBS), joint pain, stomach ulcers, weight loss, seasickness, toothaches, difficulty swallowing, alcoholism, malaria, and fever.

Some people apply capsicum to the skin for pain caused by shingles, osteoarthritis, rheumatoid arthritis, fibromyalgia, diabetes, HIV, and a certain condition that causes facial pain (trigeminal neuralgia). It is also used for muscular pain, back pain, and pain after surgery.

Some people apply capsicum to relieve muscle spasms, for skin eruptions (prurigo nodularis), to prevent nausea and vomiting after surgery, as a gargle for laryngitis, and to discourage thumb-sucking or nail-biting.

Some people put capsicum inside the nose to treat hay fever, migraine headache, cluster headache, and sinus infections (sinusitis).

One form of capsicum is currently being studied as a drug for migraine, osteoarthritis, and other painful conditions.

A particular form of capsicum causes intense eye pain and other unpleasant effects when it comes in contact with the face. This form is used in self-defense pepper sprays.

Peru is thought to be the country with the highest cultivated Capsicum diversity since varieties of all five domesticates are commonly sold in markets in contrast to other countries. Bolivia is considered to be the country where the largest diversity of wild Capsicum peppers are consumed. Bolivian consumers distinguish two basic forms: ulupicas, species with small round fruits including Capsicum eximium, Capsicum cardenasii, Capsicum eshbaughii, and Capsicum caballeroi landraces; and arivivis, with small elongated fruits including Capsicum baccatum var. baccatum and Capsicum chacoense varieties ⁹⁾.

Hot red peppers contain pungent compounds called capsaicinoids. These include capsaicin, dihydrocapsaicin, nordihydrocapsaicin, and trace amounts of other compounds. Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide) is the major pungent agent, responsible for about 70% of the burn, of hot red peppers. The newly bred nonpungent red pepper variety, CH-19 Sweet (Capsicum annuum L.), contains capsinoids. These are nonpungent capsaicin analogs and include capsiate, dihydrocapsiate, and nordihydrocapsiate. Capsiate is the primary capsinoid present in CH-19 Sweet peppers ¹⁰⁾.

The fruit of most species of capsicum contains Capsaicin (trans-8-methyl-N-vanillyl-6-nonenamide), a lipophilic chemical responsible for making chilli peppers hot when eaten. Capsaicin can produce a strong burning sensation (pungency or spiciness) in the mouth of the unaccustomed eater ¹¹⁾. Along with other related compounds, capsaicin belongs to a group of chemicals identified as capsaicinoids. Capsaicin produces a burning sensation when a tissue comes into contact with it. This occurs via binding to transient receptor potential vanilloid 1 (TRPV1) receptor (sensory receptors responsible for sending signals that cause the perception of pain), which controls movement of sodium and calcium ions across the cell membrane, which can be stimulated by heat and physical abrasion. Binding of capsaicin to transient receptor potential vanilloid 1 (TRPV1) results in a similar burning sensation. Initially, binding opens the ion channel (influx of sodium and calcium ions), causing depolarization and the production of action potentials, which are usually perceived as itching, pricking, or burning sensations. Repeated Capsaicin applications or high concentrations give rise to a long-lasting effect, which has been termed ‘defunctionalisation’, probably owing to a number of different effects that together overwhelm the cell’s normal functions, and can lead to reversible degeneration of nerve terminals ¹²⁾.

Capsaicin is a chili pepper extract with analgesic properties. Capsaicin is a neuropeptide releasing agent selective for primary sensory peripheral neurons. Used topically, capsaicin aids in controlling peripheral nerve pain ¹³⁾. Capsaicin has been used experimentally to manipulate substance P and other tachykinins. In addition, capsaicin may be useful in controlling chemotherapy- and radiotherapy-induced mucositis. As a topical medication, capsaicin has been used for neuralgias and psoriasis. Several similar compounds are currently being tested in clinical trials.

The secretion of capsaicin protects the fruit from consumption by insects and mammals, while the bright colors attract birds that will disperse the seeds. Besides capsaicin use as a food additive in various spicy cuisines, capsaicin is currently utilized for therapeutic purposes to treat various peripheral painful conditions such as rheumatoid arthritis and diabetic neuropathy ¹⁴⁾.

The capsaicin content of green and red peppers ranges from 0. 1 to 1% ¹⁵⁾. Capsaicin evokes numerous biological effects and thus has been the target of extensive investigations since its initial identification in 1919. One of the most recognized physiological properties of capsaicin is its selective effects on the peripheral part of the sensory nervous system, particularly on the primary afferent neurons. The compound is known to deplete the neurotransmitter of painful impulses known as substance P from the sensory nerve terminals, which provides a rationale for its use as a versatile experimental tool for studying pain mechanisms and also for pharmacotherapy to treat some peripheral painful states, such as rheumatoid arthritis, post-herpetic neuralgia, post-mastectomy pain syndrome and diabetic neuropathy. Considering the frequent consumption of capsaicin as a food additive and its current therapeutic application, correct assessment of any harmful effects of this compound is important from the public health standpoint. Ingestion of large amounts of capsaicin has been reported to cause histopathological and biochemical changes, including erosion of gastric mucosa and hepatic necrosis. However, there are contradictory data on the mutagenicity of capsaicin. A recent epidemiological study conducted in Mexico revealed that consumers of chili pepper were at higher risk for gastric cancer than non-consumers. However, it remains unclear whether capsaicin present in hot chili pepper is a major causative factor in the cause of gastric cancer in humans. A growing number of recent studies have focused on anticarcinogenic or antimutagenic phytochemicals, particularly those included in human diet. In summary, capsaicin has dual effects on chemically induced carcinogenesis and mutagenesis. Although a minute amount of capsaicin displays few or no deleterious effects, heavy ingestion of the compound has been associated with necrosis, ulceration and even carcinogenesis ¹⁶⁾. Capsaicin is considered to be metabolized by cytochrome P-450-dependent mixed-function oxidases to reactive species ¹⁷⁾.

Most of the capsaicin in a pungent (hot) pepper is concentrated in blisters on the epidermis of the interior ribs (septa) that divide the chambers, or locules, of the fruit to which the seeds are attached ¹⁸⁾. A study on capsaicin production in fruits of Capsicum chinense showed that capsaicinoids are produced only in the epidermal cells of the interlocular septa of pungent fruits, that blister formation only occurs as a result of capsaicinoid accumulation, and that pungency and blister formation are controlled by a single locus, Pun1, for which there exist at least two recessive alleles that result in non-pungency of Capsicum chinense fruits ¹⁹⁾. The seeds themselves do not produce any capsaicin, although the highest concentration of capsaicin can be found in the white pith around the seeds ²⁰⁾.

The amount of capsaicin in hot peppers varies significantly among varieties, and is measured in Scoville heat units (SHU). The world’s current hottest known pepper as rated in SHU is the ‘Carolina Reaper,’ which had been measured at over 2,200,000 SHU.

The amount of capsaicin in the fruit is highly variable and dependent on genetics and environment, giving almost all types of Capsicum varied amounts of perceived heat. Chili peppers are of great importance in Native American medicine, and capsaicin is used in modern medicine—mainly in topical medications—as a circulatory stimulant and analgesic. In more recent times, an aerosol extract of capsaicin, usually known as capsicum or pepper spray, has become used by law enforcement as a nonlethal means of incapacitating a person, and in a more widely dispersed form for riot control, or by individuals for personal defense. Pepper in vegetable oils, or as an horticultural product can be used in gardening as a natural insecticide ²¹⁾.

Although black pepper causes a similar burning sensation, it is caused by a different substance—piperine.

Figure 1. Capsicum pepper

Figure 2. Flowers and fruits of the Andean capsicum

Footnotes: Flowers and fruits of the Andean (A–G), Caatinga (H, I), Flexuosum (J–M) and Bolivian (N–Q) clades. (A, B) Capsicum dimorphum flower (A) and fruit (B). (C, D) Capsicum geminifolium flower (C) and fruit (D). (E, F) Different accessions of C. rhomboideum showing variations in corolla shape (rotate-campanulate in E vs. campanulate in F) and flower arrangement (solitary flowers in E vs. multi-flowered fascicles in F); pedicels always non-geniculate. (G) Capsicum lanceolatum flowering branch showing non-geniculate pedicels and white and violet corollas. (H) Capsicum caatingae fascicle of immature fruits (note the toothless calyx). (I) Capsicum parvifolium flower and immature fruit. (J–L) Capsicum flexuosum flower (J), fruiting branch, showing red pendant mature fruits (K) and blackish brown seeds (L). (M) Capsicum aff. flexuosum flower. (N, O) Capsicum caballeroi flower (N) and mature fruit (O) showing fully yellow corolla, non-geniculate pedicels and red pericarp. (P, Q) Capsicum minutiflorum flower (P) and mature dark red fruit (Q).

Figure 3. Flowers and fruits of the Longidentatum capsicum

Footnotes: Flowers and fruits of the Longidentatum (A), Atlantic (B–I), Purple Corolla (J–K), Pubescens (L, M), Baccatum (N, O) and Annuum (P, Q) clades. (A) Capsicum longidentatum fruit. (B) Capsicum cornutum flower with stellate corolla and geniculate pedicel. (C) Capsicum pereirae flower with spotted stellate corolla. (D) Capsicum friburgense urceolate-campanulate corolla and pedicel geniculate. (E) Capsicum mirabile stellate corolla with dark red spots. (F) Capsicum hunzikerianum flower with spotted stellate corolla. (G, H) Capsicum sp. nov. (GEB & CCG 3637) stellate corolla with golden-green spots (G) and mature greenish-golden yellow fruit, without well-developed calyx teeth (H). Note the different patterns of spots in the corolla in C and E–G. (I) Capsicum villosum var. muticum immature fruit; note the absence of well-developed teeth. (J) Capsicum cardenasii pendant flower with shortly tubular corolla and non-geniculate flowering pedicel. (K) Capsicum eximium flower with stellate corolla. (L, M) Capsicum pubescens flower (L) and longitudinal section of a mature fruit showing large blackish brown seeds (M). (N) Capsicum baccatum var. pendulum flower showing the distinctive green spots in the corolla. (O) Capsicum chacoense flower showing immaculate white corolla and geniculate flowering pedicel. (P) Capsicum annuum var. annuum flowering and fruiting branch showing typical white corolla and entire calyx without well-developed teeth. (Q) Capsicum chinense flowering branch showing pendant flowers with non-geniculate flowering pedicels and entire calyx without well-developed teeth.

Capsicum nutrition

Capsicums are highly nutritious. They have more vitamin C than an orange, and a typical bell pepper contains more than 100% of the daily recommended value for vitamin C. Capsicums also have relatively high amounts of vitamin B6 (Pyridoxine). Fresh capsicum fruit is 94% water. Dried capsicum fruit has a much different nutritional value due to the dehydration and concentration of vitamins and minerals.

Table 1. Capsicum sweet, green and raw nutrition facts

Table 2. Capsicum sweet, yellow and raw nutrition facts

Capsicum health benefits

In addition to the use of capsicum fruits as a food additive, in traditional medicine, capsicum has been used for the treatment of cough, toothache, sore throat, parasitic infections, rheumatism, wound healing ²⁶⁾ and also utilized as an antiseptic, counterirritant, appetite stimulator ²⁷⁾, antioxidant and immunomodulator ²⁸⁾ (Figure 4). Other effects such as antibacterial and anticancer are also related to chilies ²⁹⁾. Red pepper as a drug is given in atonic dyspepsia and flatulence ³⁰⁾ due to increasing the motility in the gastric antrum, duodenum, proximal jejunum and colon ³¹⁾. It can also increase parietal, pepsin, and bile acid secretions ³²⁾. Chilies are known to protect against gastrointestinal ailments ³³⁾ including dyspepsia ³⁴⁾, loss of appetite, gastroesophageal reflux disease and gastric ulcer ³⁵⁾ due to the several mechanisms such as reducing the food transition time through the gastrointestinal tract and anti-Helico pylori effects ³⁶⁾. Moreover, the leaves of its plant have antioxidant activity ³⁷⁾.

Hot red peppers consist of spicy compounds called capsaicinoids which include capsaicin, dihydrocapsaicin, nordihydrocapsaicin and other compounds ³⁸⁾ (Figure 4).

Figure 4. Chemical structures of capsaicinoids

Figure 5. Chemical structures of capsaicin and capsiate

Capsaicin, water-insoluble derivative of homovanillic acid ⁴¹⁾ and the main active ingredient in capsicum fruits, is responsible for hot sensation to the tongue ⁴²⁾ and is utilized for the treatment of inflammatory disorders such as psoriasis and rheumatoid arthritis ⁴³⁾, diabetic neuropathy, postherpetic neuralgia, cluster headache, postmastectomy syndrome, reflex sympathetic dystrophy ⁴⁴⁾, dermatitis or eczema itching ⁴⁵⁾, postoperative nausea and vomiting, bladder hyperactivity ⁴⁶⁾, gallstone ⁴⁷⁾, anorexia, haemorrhoids, liver congestion, foodborne gastrointestinal pathogens including Listeria monocytogenes, Salmonella typhimurium and Bacillus cereus ⁴⁸⁾, tonsillitis and rhinitis and fibromyalgia ⁴⁹⁾. It is also used as pesticides ⁵⁰⁾, analgesic, antiobesity, antihypertensive ⁵¹⁾, antiarrhythmic, antiischemic ⁵²⁾, and gastroprotective agent ⁵³⁾. It can stimulate saliva and digestive enzymes of the pancreas, small intestine ⁵⁴⁾, and also stimulate hair growth in alopecia areata. Anticoagulant activity, prevention of aspiration pneumonia ⁵⁵⁾, protecting neuromuscular junctions from Clostridium botulinum neurotoxin A and improving cognitive function are also attributed to capsaicin beneficial properties ⁵⁶⁾.

Topically applied capsaicin is used in migrane, trigeminal neuralgia, herpes zoster ⁵⁷⁾, chronic musculoskeletal pain (26) and skin disorders ⁵⁸⁾.

Different studies indicated that red pepper and its active constituent, capsaicin, have therapeutic potential in different components of metabolic syndrome.

Capsicum likely effective for:

• Nerve damage related to diabetes. Some research shows that applying a cream or using a skin patch containing capsaicin, the active chemical found in capsicum, reduces pain in people with nerve damage caused by diabetes. A specific cream containing 0.075% capsaicin (Zostrix-HP, Link Medical Products Pty Ltd.) is approved by the US Food and Drug Administration (FDA) for treating this condition. Creams or gels that contain less capsaicin don’t seem to work.
• Pain. Applying creams and lotions containing capsaicin, the active chemical in capsicum, can temporarily relieve chronic pain from several conditions, including rheumatoid arthritis, osteoarthritis, back pain, jaw pain, psoriasis, and other conditions.
• Nerve damage caused by shingles. Applying a patch containing 8% capsaicin (Qutenza, NeurogesX Inc.), the active chemical in capsicum reduces pain over 24 hours by 27% to 37% for in people with nerve damage caused by shingles. This capsaicin patch is approved by the US Food and Drug Administration (FDA) for this use. It is only available by prescription.

Capsicum possibly effective for:

• Back pain. Some research shows that applying a plaster that contains capsicum to the back can reduce low back pain.
• Cluster headache. Some research shows that applying capsaicin, the active chemical in capsicum, inside the nose reduces the number and severity of cluster headaches. It’s best to apply capsicum to the nostril that is on the same side of the head as the headache.
• Runny nose not caused by allergies or infection (non-allergic rhinitis or perennial rhinitis). Research shows that applying capsaicin, the active chemical in capsicum, inside the nose can reduce runny nose in people without allergies or an infection. The benefits might last for 6-9 months.
• Preventing nausea and vomiting after surgery. Research shows that applying a plaster containing capsicum to specific points on the hand and forearm 30 minutes before anesthesia and leaving it in place for 6-8 hour daily for up to 3 days after surgery reduces nausea and vomiting after surgery.
• Pain after surgery. Research shows that applying a plaster containing capsicum to specific points on the hand and forearm 30 minutes before anesthesia and leaving it in place for 6-8 hour daily for up to 3 days after surgery reduces the need for painkillers within the first 24 hours after surgery.

Insufficient evidence to rate effectiveness for:

• Hay fever (allergic rhinitis). Early research suggests that inserting cotton wads in the nose that have been soaked in the capsicum active chemical capsaicin for 15 minutes and repeated over two days might reduce hay fever symptoms. But there is conflicting evidence that this might not improve symptoms.
• Burning mouth syndrome. Early research shows that using a mouth rinse containing capsaicin, the active chemical in capsicum, daily for 7 days slightly decreases burning discomfort in people with burning mouth syndrome.
• Heartburn. Early research suggests that red pepper powder (containing capsicum) in capsules taken 3 times daily before meals reduces symptoms of heartburn. But in some people, symptoms get worse before they get better.
• Exercise performance. Research shows that taking a supplement containing capsicum and other ingredients before exercise does not improve exercise performance in men.
• Fibromyalgia. Applying a cream containing 0.025% to 0.075% capsaicin, the active chemical in capsicum, 4 times daily to tender points might reduce tenderness in people with fibromyalgia. However, it doesn’t seem to reduce overall pain or improve physical function.
• Nerve damage caused by HIV. Some research suggest that applying a patch containing 8% capsaicin, the active chemical in capsicum, to the skin for 30-90 minutes reduce pain for up to 12 weeks in people with nerve damage caused by HIV. But other research suggests it might not provide any benefits. Applying cream containing 0.075% capsaicin does not seem to work.
• Irritable bowel syndrome (IBS). Early research shows that capsicum fruit taken by mouth does not help symptoms of IBS.
• Joint pain. Early research shows that taking capsules of a specific combination product containing capsaicin, the active ingredient in capsicum, and many other ingredients (Instaflex Joint Support) daily for 8 weeks reduces joint pain by about 21% compared to placebo. The effects of capsicum alone cannot be determined from this study.
• Migraine headache. Some reports suggest that using the active chemical in capsicum in the nose might help migraine headaches.
• Muscular pain. Early research shows that using a specific cream (Dipental Cream) that contains capsaicin, an active chemical in capsicum, in addition to a ketoprofen patch does not further relieve pain in people with muscular pain in the upper back.
• Stomach ulcers. People who eat capsicum fruit (chili) an average of 24 times per month appear to be less likely to have an ulcer than people who eat chili an average of 8 times per month. This applies to chili in the form of chili powder, chili sauce, curry powder, and other chili-containing foods. But there is other evidence that suggests eating chili peppers does not help heal ulcers.
• A skin condition called prurigo nodularis. Applying a cream containing capsaicin, the active chemical in capsicum, 4-6 times daily seems to relieve burning sensations, itching and other symptoms. But it may take 22 weeks to 33 months of treatment to see a benefit, and symptoms may return after stopping use cream.
• Polyps in the nose. Early research shows that putting capsicum in the nose improves symptoms and airflow in people with polyps.
• Swallowing difficulties. Some people, especially elderly people or those who have suffered a stroke, are more likely than other people to develop “aspiration pneumonia.” This is a kind of pneumonia that develops after food or saliva is sucked into the airways because the person couldn’t swallow properly. There is some evidence that dissolving a capsaicin-containing lozenge in the mouth of elderly people with swallowing problems before each meal can improve their ability to swallow.
• Weight loss. Some research shows that taking capsules containing capsicum twice daily 30 minutes before eating for 12 weeks reduces stomach fat but not weight in overweight and obese people. But other research shows that taking a combination supplement (Prograde Metabolism) containing capsicum extract (Capsimax, OmniActive Health Technologies) twice daily for 8 weeks reduces body weight, fat mass, waist circumference, and hip circumference when used along with a diet.
• Blood clots.
• Colic.
• Cramps.
• Fever.
• Heart disease.
• High cholesterol.
• Laryngitis.
• Muscle spasms.
• Nausea.
• Toothache.
• Other conditions.

More evidence is needed to rate the effectiveness of capsicum for these uses.

Capsicum effects on obesity

Abnormal metabolism of energy had led to storage of excess energy in fat cells. This is considered as obesity, another component of the metabolic syndrome, which is the most widespread disease ⁵⁹⁾.

Several studies reported that red chili pepper exhibited anti-obesity effect by different mechanisms including thermogenesis, satiety, fat oxidation ⁶⁰⁾, elevation of energy expenditure ⁶¹⁾, reduction of energy intake ⁶²⁾, prevention of adipogenesis ⁶³⁾, restriction the activity of lipoprotein lipase ⁶⁴⁾ and pancreatic lipase ⁶⁵⁾, stimulation of lipolysis in adipose tissue ⁶⁶⁾, inhibition of the differentiation of adipocytes ⁶⁷⁾ and modulating adipokine release from adipose tissues ⁶⁸⁾. For examples, in animal studies, capsaicin exhibited antiobesity effects via inhibition of the generation white fat cells and restricted the activity of lipoprotein lipase ⁶⁹⁾.

Different clinical investigations showed that foods containing capsaicin increased fat oxidation and energy expenditure especially at high doses, promoted negative energy balance and restrained orexigenic sensations such as hunger and desire to eat ⁷⁰⁾ whether they received an oral or non-oral capsaicin ⁷¹⁾. This study also showed that capsaicin increased core body and skin temperature, however, the magnitude of its thermogenic and appetitive effects is small ⁷²⁾.

Moreover, when red pepper was added to breakfast in 13 healthy Japanese females (age 25.8 ± 2.8 years, weight 54.2 ±6.4 kg, height 1.57 ± 0.04 m, body fat 25.3 ± 4.7%), protein and fat intakes at lunch time decreased but when it used as appetizer, carbohydrate and energy intakes at lunch time decreased in 10 healthy Caucasian males (age 32.9 ±7.8 years, weight 72.5± 10.1 kg, height 1.75±0.06m) ⁷³⁾.

Male and female Japanese has the same response in decreasing fat intake, this is dissimilar to Caucasians ⁷⁴⁾.

Study on the effect of dietary red pepper on energy metabolism in 13 Japanese female have shown that adding of the red pepper to high-fat meals, increased brown adipose tissue thermogenesis ⁷⁵⁾ induced by β adrenergic stimulation ⁷⁶⁾, and lipid oxidation ⁷⁷⁾. However, addition to high carbohydrate meals resulted in increasing the oiliness of the meal ⁷⁸⁾.

The findings of a study on 10 healthy men and 17 healthy women (mean age 26.9±6.3 years, mean BMI 22.2±2.7 kg/m²) for 6 weeks (3 weeks of positive energy balance and 3 weeks of negative energy balance) showed that the ingestion of capsaicin in combination with green tea caused significant reduction of energy intake in positive energy balance, increased satiety and restrained hunger in negative energy balance more than ingestion of capsaicin alone. In this study during negative energy balance body weight was decreased by 0.44 ± 0.2 kg, thus, it may be helpful in weight loss ⁷⁹⁾.

A single blind, randomized, crossover study which was conducted on 19 healthy women and 11 healthy men (BMI 20-30 kg/m², age 18-60 years) suggested that an acute lunch consist of capsaicin, increased plasma GLP1 and decreased plasma ghrelin concentrations, but, it had no impact on satiety, energy expenditure and peptide YY ⁸⁰⁾.

A randomized double-blind, placebo-controlled, cross-over study suggested that 4-week supplementation with 1g/day of red pepper spice in 62 obese females with the body mass index ≥27 kg/m² and the age of 40-75 years indicated that this culinary amount of red pepper, did not change inflammation in systematically inflamed obese females ⁸¹⁾.

In a clinical trial, administration of capsaicinoids for 12 weeks at a dose of 6 mg/day in subjects with the age of 42 years and BMI 30.4, confirmed the effect of capsaicin on abdominal fat reduction ⁸²⁾.

According to the results of a study on 11 healthy volunteers, CH-19 sweet (a non-pungent cultivar of red pepper) can increase thermogenesis and energy consumption, less than that of observed in hot red pepper ⁸³⁾.

So, it could be suggested that the differences in red pepper’s colors and pungency led to different energy homeostasis ⁸⁴⁾.

According to clinical studies, the antiobesity mechanism of capsaicin is partially similar to phentermine, an anti-obesity drug, which both increased energy expenditure and decreased food intake. Orlistat, another antiobesity drug, has pancreatic lipase inhibitory activity, which is in common with one of the antiobesity mechanism of capsaicin. Orlistat (75 mg/kg/d) has better ability in controlling of weight gain than capsaicin (30 mg/kg/d) in rats fed a high fat diet for 5 weeks.

Taken together, these observations reinforce the idea that consumption of red chili pepper containing capsaicin, capsaicinoids and capsinoids could play beneficial effects in weight management via increase energy expenditure, satiety, fat oxidation and thermogenesis which are the main mechanisms of antiobesity effect of capsaicin (Table 3).

However, to aid weight management, additional investigation is warranted to explore: 1) the sustainability of energy balance effects; 2) the need to alter dose, form, and/or composition to improve long-term efficacy; 3) the combination of capsaicin and capsiate with other weight management strategies; and 4) the mechanisms by which capsaicin and capsiate can be most successfully incorporated into the diet.

Although capsaicin intake appears to be a safe practice, further studies will be needed to ascertain the safety of regular long-term consumption.

Table 3. Summary of the effects of Capsicum annuum and capsaicin on obesity

Abbreviations: HFD = high fat diet; HCD = high carbohydrate diet; G3PD = glycerol 3 phosphate dehydrogenase; BAT = brown adipose tissue; GLP1 = glucagon-like peptide-1

Capsaicin for non‐allergic rhinitis

Rhinitis means inflammation of the nose. It affects 30% to 40% of the general population. There are many forms of rhinitis: rhinosinusitis (or simply sinusitis), allergic rhinitis and non-allergic rhinitis. Patients are diagnosed with non-allergic rhinitis when anatomic, infectious and allergic causes have been excluded and also do not have sinusitis ⁹⁹⁾. Non-allergic rhinitis symptoms include congestion of the nose, a blocked or obstructed sensation in the nose that causes difficulty breathing, clear nasal discharge (runny nose), sneezing and less frequently, nasal itching, can range from mild to debilitating. Non-allergic rhinitis affects between 25% and 50% of patients with rhinitis. There are several subtypes of non-allergic rhinitis: occupational (from exposure to chemicals), smoking, gustatory (related to eating food or drinking fluid), hormonal (from changes in hormone levels in the body), pregnancy, senile or elderly (mostly affecting the older population), medication-induced (for example, from overuse of decongestant nasal sprays) and local allergic (local allergy in the nose, while skin or blood allergy tests are negative). The most common subtype of non-allergic rhinitis is ‘idiopathic’ or ‘vasomotor’ rhinitis, which results from imbalance of the neural (nerve) system that manages the function of the nose. The mechanisms of many of these subtypes remain unknown. Non-allergic rhinitis affects about 25% to 50% of patients with rhinitis and is therefore very common.

Several medications are widely used in the treatment of non-allergic rhinitis, including oral and topical nasal antihistamines, intranasal and (rarely) systemic corticosteroids, and anticholinergics. Capsaicin, the active component of chili peppers, delivered intranasally, is considered a treatment option for non-allergic rhinitis.

Capsaicin affects the unmyelinated peptidergic sensory C fibres of the nasal mucosa, which are highly sensitive to it ¹⁰⁰⁾. It is hypothesised that repeated high doses of capsaicin lead to degeneration of these nerve fibres. Unmyelinated sensory C fibres play a role in neurogenic reflex mechanisms in the nasal mucosa, both local and central. Stimulation of these sensory fibres by non-specific stimuli can lead to a local reflex in the nasal mucosa with a release of neuropeptides (C-peptide, CGRP, VIP). At the same time, capsaicin does not affect the number of inflammatory cells in the nasal mucosa long-term ¹⁰¹⁾. The same study also did not show a difference in neuronal tissue density as expressed by synaptophysin or neurofilament staining.

Although these mechanisms are not considered definitive, several studies have demonstrated a significant improvement of nasal symptoms after topical administration of capsaicin ¹⁰²⁾.

Intranasal capsaicin is currently considered one of the treatment options for non-allergic rhinitis. Capsaicin is also one of the active ingredients (along with eucalyptus oil) in Sinus Buster, an over-the-counter nasal spray available in the United States ¹⁰³⁾. The dose and frequency of intranasal capsaicin application have varied significantly in studies. Doses of capsaicin have ranged from 0.1 to 100 mg per application, given through one or several actuations of the spray depending on the capsaicin preparation in a particular study ¹⁰⁴⁾. The regimen of capsaicin treatment has also ranged widely from five times during the same day, to three times per day for three days, to once daily for five days, or once every two to three days for seven treatments. The local pharmacology of capsaicin in the nose is poorly understood. It is metabolised in the liver.

The side effects of using capsaicin in the nose include irritation, burning, sneezing and coughing, however there are no known long-term side effects of capsaicin use. Capsaicin is given in the form of brief treatments, usually during the same day. It works by down-regulating transient receptor potential vanilloid receptor expression on C-sensory fibres. Transient receptor potential vanilloid represents special ion channels involved in the sensations of pain, cold, hotness, tastes, pressure and vision. C fibres help to conduct some of these sensations. There is ongoing research into the effects of capsaicin on these mechanisms and its clinical uses.

A 2015 Cochrane Review found that Capsaicin may be an option in the treatment of idiopathic non-allergic rhinitis ¹⁰⁵⁾. Capsaicin is given in the form of brief treatments, usually during the same day. Capsaicin appears to have beneficial effects on overall nasal symptoms up to 36 weeks after treatment, based on a few, small studies (low-quality evidence). Well-conducted randomised controlled trials are required to further advance our understanding of the effectiveness of capsaicin in non-allergic rhinitis, especially in patients with non-allergic rhinitis of different types and severity, and using different methods of capsaicin application.

Interestingly, intranasal capsaicin has also been studied in allergic rhinitis. However, a 2006 Cochrane review on capsaicin in allergic rhinitis in adults did not find an evidence of intranasal capsaicin effect ¹⁰⁶⁾.

Capsaicin applied to the skin for chronic neuropathic pain in adults

Neuropathic pain is “pain caused by a lesion or disease of the somatosensory system” ¹⁰⁷⁾. Neuropathic pain is a consequence of a pathological maladaptive response of the nervous system to ‘damage’ from a wide variety of potential causes. It is characterized by pain in the absence of a noxious stimulus and may be spontaneous (continuous or paroxysmal) in its temporal characteristics or be evoked by sensory stimuli (dynamic mechanical allodynia where pain is evoked by light touch of the skin). Neuropathic pain is associated with a variety of sensory loss (numbness) and sensory gain (allodynia) clinical phenomena, the exact pattern of which vary between person and disease, perhaps reflecting different pain mechanisms operating in an individual person and therefore potentially predictive of response to treatment ¹⁰⁸⁾. Preclinical research hypothesises a bewildering array of possible pain mechanisms that may operate in people with neuropathic pain, which largely reflect pathophysiological responses in both the central and peripheral nervous systems, including neuronal interactions with immune cells ¹⁰⁹⁾. Overall, even the most effective of available drugs provide only modest benefit in treating neuropathic pain ¹¹⁰⁾, and a robust classification of neuropathic pain is not yet available ¹¹¹⁾.

Neuropathic pain is usually divided according to the cause of nerve injury. There may be many causes, but common causes of neuropathic pain include diabetes (painful diabetic neuropathy), shingles (postherpetic neuralgia), amputation (phantom limb pain), neuropathic pain after surgery or trauma, stroke or spinal cord injury, trigeminal neuralgia, and HIV infection. Sometimes the cause is not known.

Many people with neuropathic pain conditions are significantly disabled with moderate or severe pain for many years. Chronic pain conditions comprised five of the 11 top-ranking conditions for years lived with disability in 2010 ¹¹²⁾, and are responsible for considerable loss of quality of life, employment, and increased healthcare costs ¹¹³⁾.

In systematic reviews, the overall prevalence of neuropathic pain in the general population is reported to be between 7% and 10% ¹¹⁴⁾, and about 7% in one systematic review of studies published since 2000 ¹¹⁵⁾. In individual countries, prevalence rates have been reported as 3.3% in Austria ¹¹⁶⁾, 6.9% in France ¹¹⁷⁾, and up to 8% in the UK ¹¹⁸⁾. Some forms of neuropathic pain are increasing, particularly painful diabetic neuropathy and postsurgical chronic pain (which is often neuropathic in origin) ¹¹⁹⁾. The prevalence of postherpetic neuralgia is likely to fall if vaccination against the herpes virus becomes widespread.

Estimates of incidence vary between individual studies for neuropathic pain associated with particular conditions, often because of small numbers of cases. In primary care in the UK between 2002 and 2005, the incidences (per 100,000 person-years’ observation) were 28 for postherpetic neuralgia, 27 for trigeminal neuralgia, 0.8 for phantom limb pain, and 21 for painful diabetic neuropathy ¹²⁰⁾. Other research groups have estimated an incidence of 4 in 100,000 per year for trigeminal neuralgia ¹²¹⁾, and of 12.6 per 100,000 person-years for trigeminal neuralgia and 3.9 per 100,000 person-years for postherpetic neuralgia in one study of facial pain in the Netherlands ¹²²⁾.

Neuropathic pain is difficult to treat effectively, with only a minority of people experiencing a clinically relevant benefit from any one intervention. A multidisciplinary approach is now advocated, with pharmacological interventions being combined with physical or cognitive interventions, or both. Conventional analgesics are usually thought to be ineffective, but without evidence to support or refute that view. Some people with neuropathic pain may derive some benefit from a topical lidocaine patch or low-concentration topical capsaicin, though evidence about benefits is uncertain ¹²³⁾. The earlier review of high-concentration topical capsaicin indicated benefit in some people with postherpetic neuralgia ¹²⁴⁾. Treatment for neuropathic pain is more usually with so-called unconventional analgesics (pain modulators), for example, with antidepressants such as duloxetine and amitriptyline ¹²⁵⁾, or antiepileptic drugs such as gabapentin or pregabalin ¹²⁶⁾.

The proportion of people who achieve worthwhile pain relief (typically at least 50% pain intensity reduction) ¹²⁷⁾ with any one intervention is small, generally only 10% to 25% more than with placebo, with numbers needed to treat for an additional beneficial outcome usually between 4 and 10 ¹²⁸⁾. Neuropathic pain is not particularly different from other chronic pain conditions in that only a small proportion of trial participants have a good response to treatment ¹²⁹⁾.

The current National Institute for Health and Care Excellence ¹³⁰⁾ guidance for the pharmacological management of neuropathic pain suggests offering a choice of amitriptyline, duloxetine, gabapentin, or pregabalin as initial treatment for neuropathic pain (with the exception of trigeminal neuralgia), with switching if first, second, or third drugs tried are not effective or not tolerated. This concurs with other recent guidance ¹³¹⁾.

Topical agents are most likely to be used for localized, peripheral neuropathies. Topical medications are applied externally and are taken up through the skin. They exert their effects close to the site of application, and there is no substantial systemic uptake or distribution. This compares with transdermal application, where the medication is applied externally and is taken up through the skin, but relies on systemic distribution for its effect.

Low-concentration capsaicin creams have not convincingly been shown to be effective for neuropathic pain ¹³²⁾. The initial burning sensation felt on application of capsaicin limits the amount of active substance that can be applied at one time, which necessitates frequent (four times per day) application, and reduces compliance with treatment. The high-concentration (8%) patch was developed to increase the amount of capsaicin delivered to the skin, and improve tolerability. Rapid delivery is thought to improve tolerability because cutaneous nociceptors are ‘defunctionalised’ quickly, and the single application avoids both noncompliance and contamination of the home environment with particles of dried capsaicin cream ¹³³⁾. At the present time, the 8% patch is the only high-strength formulation of capsaicin commercially available, although different strengths and formulations have been investigated in clinical trials. A capsaicin concentration of 5% or greater is considered high.

The treatment is usually applied as a single application dermal patch over the area where painful symptoms are felt. Each patch (280 cm²) contains capsaicin 640 μg/cm², and can be cut to treat smaller areas and irregular shapes, or up to four patches can be used simultaneously to treat large areas, such as the back. The skin to which patches are applied should not be broken or irritated. The skin is usually treated with a topical local anaesthetic (e.g. topical lidocaine 4% for 60 minutes) before application because the capsaicin may cause an intense burning sensation, and the anaesthetic is then washed off thoroughly, and the skin dried, before the patch is applied. Studies suggest that skin cooling is as effective as topical anaesthetic for relieving initial burning ¹³⁴⁾, or that any form of pretreatment in unnecessary ¹³⁵⁾. The patch is left in place for 30 minutes when applied to the feet, or 60 minutes for other areas, before removal and careful cleansing of the skin with a specially formulated cleanser, to remove any residual capsaicin. Application must be carried out in a healthcare centre by trained personnel, and patients are usually monitored for up to two hours after treatment. Stringent conditions are required, and as well as using trained healthcare professionals, the treatment setting needs to be well ventilated and spacious due to the vapour of the capsaicin, and cough due to inhalation of capsaicin particles or dust is a hazard for both the healthcare professionals and the patients. Treatment can be repeated after 12 weeks if necessary.

High-concentration capsaicin is available by prescription only; it was first licensed in Europe and the US in 2009. It was originally licensed in the European Union to treat neuropathic pain in patients without diabetes, but in 2015 the restriction on patients with diabetes was lifted. In the US, it is licensed only to treat postherpetic neuralgia. The US Food and Drug Administration refused a license for neuropathic pain in HIV in 2012.

Topical creams with capsaicin are used to treat peripheral neuropathic pain. Following application to the skin, capsaicin causes enhanced sensitivity, followed by a period with reduced sensitivity and, after repeated applications, persistent desensitisation. High-concentration (8%) capsaicin patches were developed to increase the amount of capsaicin delivered; rapid delivery was thought to improve tolerability because cutaneous nociceptors are ‘defunctionalised’ quickly. The single application avoids noncompliance. Only the 8% patch formulation of capsaicin is available, with a capsaicin concentration about 100 times greater than conventional creams. High-concentration topical capsaicin is given as a single patch application to the affected part. It must be applied under highly controlled conditions, often following local anaesthetic, due to the initial intense burning sensation it causes. The benefits are expected to last for about 12 weeks, when another application might be made.

A 2017 Cochcrane Review found moderate quality evidence that high-concentration (8%) capsaicin patches can give moderate pain relief, or better, to a minority of people with postherpetic neuralgia, and very low quality evidence that it benefits those with HIV-neuropathy and peripheral diabetic neuropathy ¹³⁶⁾.

Capsicum dosage

The following doses have been studied in scientific research:

Applied to the skin:

• For nerve damage related to diabetes: A specific cream (Zostrix-HP, Link Medical Products Pty Ltd.) containing 0.075% capsaicin, the active chemical in capsicum, has been used 4 times daily for 8 weeks. Also, a specific patch (Qutenza, NeurogesX Inc.) containing 8% capsaicin has been applied once for 60-90 minutes.
• For nerve damage caused by shingles: A specific patch (Qutenza, NeurogesX Inc.) containing 8% capsaicin, the active chemical in capsicum, has been applied once for 60-90 minutes.
• For low back pain: Capsicum-containing plasters providing 11 mg of capsaicin per plaster or 22 mcg of capsaicin per square centimeter of plaster have been used. The plaster is applied once daily in the morning and left in place for 4-8 hours.
• For preventing nausea and vomiting after surgery: Capsicum-containing plasters have been used on acupoints on the hand and forearm for 30 minutes before anesthesia and left in place for 6-8 hours daily for up to 3 days.
• Preventing pain after surgery: Capsicum-containing plasters have been used on acupoints on the hand and forearm for 30 minutes before anesthesia and left in place for 6-8 hours daily for up to 3 days.

Be sure to wash your hands after applying capsaicin cream. A diluted vinegar solution works well. You won’t be able to get the capsaicin off with just water. Don’t use capsicum preparations near the eyes or on sensitive skin. It could cause burning.

Inside the nose:

• For cluster headache: 0.1 mL of a 10 mM capsaicin suspension, providing 300 mcg/day of capsaicin, applied to the nostril on the painful side of the head. Apply the suspension once daily until the burning sensation disappears. A capsaicin 0.025% cream (Zostrix, Rodlen Laboratories) applied daily for 7 days has been used to treat acute cluster headache attacks.
• For runny nose not caused by allergies or infection (perennial rhinitis): Solutions containing capsaicin, the active chemical in capsicum, have been applied inside the nose 3 times per day for 3 days, every other day for 2 weeks, or once weekly for 5 weeks.

Putting capsaicin in the nose can be very painful, so a local painkilling medicine such as lidocaine is often put into the nose first.

Capsicum side effects

Capsicum is likely safe when consumed in amounts typically found in food. Side effects can include stomach irritation and upset, sweating, flushing, and runny nose. Adverse events from capsaicin are mainly at the application site (burning, stinging, erythema), and systemic events are rare.

Medicinal lotions and creams that contain capsicum extract are also likely safe for most adults when applied to the skin. The active chemical in capsicum, capsaicin, is approved by the FDA as an over-the-counter medication. Side effects can include skin irritation, burning, and itching. Capsicum can also be extremely irritating to the eyes, nose, and throat. Don’t use capsicum on sensitive skin or around the eyes.

Capsicum is possibly safe when taken by mouth as medicine, short-term, when applied to the skin appropriately, and when used in the nose. No serious side effects have been reported, but application in the nose can be very painful. Nasal application can cause burning pain, sneezing, watery eyes, and runny nose. These side effects tend to decrease and go away after 5 or more days of repeated use.

Capsicum is possibly UNSAFE to take by mouth in large doses or for long periods of time. In rare cases, this can lead to more serious side effects like liver or kidney damage, as well as severe spikes in blood pressure.

Special precautions and warnings

Pregnancy and breast-feeding: Capsicum is likely safe when applied to the skin during pregnancy. But not enough is known about its safety when taken by mouth. Stay on the safe side and don’t use capsicum if you are pregnant.

If you are breast-feeding, using capsicum on your skin is likely safe. But it is possibly UNSAFE for your baby if you take capsicum by mouth. Skin problems (dermatitis) have been reported in breast-fed infants when mothers eat foods heavily spiced with capsicum peppers.

Children: Applying capsicum to the skin of children under two years of age is possibly UNSAFE. Not enough is known about the safety of giving capsicum to children by mouth. Don’t do it.

Bleeding disorders: While conflicting results exist, capsicum might increase the risk of bleeding in people with bleeding disorders.

Damaged or broken skin: Don’t use capsicum on damaged or broken skin.

Diabetes: In theory, capsicum might affect blood sugar levels in people with diabetes. Until more is known, monitor your blood sugar closely if you take capsicum. The dose of your diabetes medication might need to be changed.

High blood pressure: Taking capsicum or eating a large amount of chili peppers might cause a spike in blood pressure. In theory, this might worsen the condition for people who already have high blood pressure.

Surgery: Capsicum might increase bleeding during and after surgery. Stop using capsicum at least 2 weeks before a scheduled surgery.

Interactions with medications

Moderate

Be cautious with this combination.

Aspirin

Capsicum might decrease how much aspirin the body can absorb. Taking capsicum along with aspirin might reduce the effectiveness of aspirin.

Cefazolin

Capsicum might increase how much cefazolin the body can absorb. Taking capsicum along with cefazolin might increase the effects and side effects of cefazolin.

Ciprofloxacin

Capsicum might increase how much ciprofloxacin the body can absorb. Taking capsicum along with ciprofloxacin might increase the effects and side effects of ciprofloxacin.

Cocaine

Cocaine has many dangerous side effects. Using capsicum along with cocaine might increase the side effects of cocaine, including heart attack and death.

Medications for diabetes (Antidiabetes drugs)

Diabetes medications are used to lower blood sugar. Capsicum might also decrease blood sugar. Taking capsicum along with diabetes medications might cause your blood sugar to go too low. Monitor your blood sugar closely. The dose of your diabetes medication might need to be changed.

Some medications used for diabetes include glimepiride (Amaryl), glyburide (DiaBeta, Glynase PresTab, Micronase), insulin, pioglitazone (Actos), rosiglitazone (Avandia), and others.

Medications for high blood pressure (Antihypertensive drugs)

Some research shows that capsicum might increase blood pressure. In theory, taking capsicum along with medications used for lowering high blood pressure might reduce the effectiveness of these drugs.

Some medications for high blood pressure include captopril (Capoten), enalapril (Vasotec), losartan (Cozaar), valsartan (Diovan), diltiazem (Cardizem), Amlodipine (Norvasc), hydrochlorothiazide (HydroDiuril), furosemide (Lasix), and many others.

Medications that slow blood clotting (Anticoagulant / Antiplatelet drugs)

Capsicum might slow blood clotting. Taking capsicum along with medications that also slow clotting might increase the chances of bruising and bleeding.

Some medications that slow blood clotting include aspirin, clopidogrel (Plavix), diclofenac (Voltaren, Cataflam, others), ibuprofen (Advil, Motrin, others), naproxen (Anaprox, Naprosyn, others), dalteparin (Fragmin), enoxaparin (Lovenox), heparin, warfarin (Coumadin), and others.

Theophylline

Capsicum can increase how much theophylline the body can absorb. Taking capsicum along with theophylline might increase the effects and side effects of theophylline.

Warfarin (Coumadin)

Warfarin (Coumadin) is used to slow blood clotting. Capsicum might increase the effectiveness of warfarin (Coumadin). Taking capsicum along with warfarin (Coumadin) might increase the chances of bruising and bleeding. Be sure to have your blood checked regularly. The dose of your warfarin (Coumadin) might need to be changed.

Minor

Be watchful with this combination.

Medications for high blood pressure (ACE inhibitors)

Some medications for high blood pressure might cause a cough. There is one report of someone whose cough worsened when using a cream with capsicum along with these medications for high blood pressure. But is it not clear if this interaction is a big concern.

Some medications for high blood pressure include captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), ramipril (Altace), and others.

Interactions with herbs and supplements

Coca

Using capsicum (including exposure to the capsicum in pepper spray) and coca might increase the effects and risk of adverse effects of the cocaine in coca.

Herbs and supplements that might lower blood sugar

Capsicum might affect blood sugar. Using it along with other herbs and supplements that also affect blood sugar might cause blood sugar to drop too low in some people. Some of these products include bitter melon, ginger, goat’s rue, fenugreek, kudzu, willow bark, and others.

Herbs and supplements that might slow blood clotting

Capsicum might slow blood clotting. Taking capsicum with herbs and supplements that also slow clotting might increase the risk of bruising and bleeding in some people. Some herbs that slow blood clotting are angelica, clove, danshen, garlic, ginger, ginkgo, Panax ginseng, and others.

Iron

Using capsicum might reduce the ability for the body to absorb iron.

What is cat’s claw

Cat’s claw is a woody creeper vine that grows wild in the Amazon rainforest and other tropical areas of Central and South America ¹⁾. Its thorns resemble a cat’s claws. Cat’s claw is naturally distributed in South America, mainly in Peru and Brazil as well as in Central America, and it is traditionally used as a medicinal plant. The two most common Cat’s claw species are Uncaria tomentosa and Uncaria guianensis that belong to Rubiaceae family. Most commercial preparations of Cat’s claw contain Uncaria tomentosa. Using cat’s claw for health dates back to the Inca civilization. Cat’s claw historical uses have included for contraception, inflammation, cancer, and viral infections, and to stimulate the immune system. Today, cat’s claw is used as a dietary supplement for a variety of health conditions including viral infections (such as herpes and HIV), Alzheimer’s disease, cancer, arthritis, rheumatism, asthma, diverticulitis, peptic ulcers, colitis, gastritis, hemorrhoids, parasites, cirrhosis, diabetes, hypertension, stroke and leaky bowel syndrome. The bark and root of cat’s claw are used to make liquid extracts, capsules, tablets, and tea. However, there have been very few high quality clinical trials (studies done in people) of cat’s claw. And there’s no conclusive scientific evidence based on studies in people that supports using cat’s claw for any health purpose. Recently as study using Cat’s claw (Uncaria tomentosa) as adjuvant treatment was carried out with 40 patients who had undergone complete breast cancer resection, which was histologically diagnosed as Invasive Ductal Carcinoma—Stage II ²⁾. Adjuvant treatment is an additional cancer treatment given after the primary cancer treatment to lower the risk that the cancer will come back. Adjuvant therapy may include chemotherapy, radiation therapy, hormone therapy, targeted therapy, or biological therapy. The Cat’s claw (Uncaria tomentosa) dose used was 300 mg dry extract per day. The rsearch found that Cat’s claw is effective in the recovery from neutropenia induced by chemotherapy in women diagnosed with Invasive Ductal Carcinoma—Stage II. Cat’s claw (Uncaria tomentosa) enables the stimulation of the immune system, increasing resistance to diseases when the body is immunosuppressed due to stress, malnutrition, or due to the effect of some medication ³⁾.

Few side effects such as gastrointestinal complaints (nausea, diarrhea, stomach discomfort), kidney effects, nervous system disorders, and an increased risk of bleeding with anticoagulant therapy have been reported for cat’s claw when taken in small amounts. Women who are pregnant or trying to become pregnant should avoid using cat’s claw because of its past use for preventing and aborting pregnancy.

Around 50 compounds have been isolated from Cat’s claw, from which approximately 35 chemical markers can be considered exclusive to this species, including triterpenes ⁴⁾, alkaloids ⁵⁾ and polyphenols ⁶⁾. The special interest on Cat’s claw plant is due to the fact that numerous scientific studies report a wide variety of biological activities ⁷⁾, such as immunomodulatory properties ⁸⁾, as well as their antioxidant, anti-inflammatory and cardiovascular effects and protective properties against cancer, among others ⁹⁾.

Although originally attributed to alkaloids, recent studies suggest that the health effects derived from Cat’s claw could be attributed to a synergistic interaction among different chemical compounds present in this plant ¹⁰⁾. Of particular interest are polyphenols, for which there is strong evidence of having multiple molecular targets, modulating pro-inflammatory gene expression, interacting with phospholipid membranes ¹¹⁾ and modulating pathways related to chronic inflammation and energy metabolism ¹²⁾.

When considering subclasses of polyphenols, Cat’s claw barks show variable contents, with procyanidin dimers as the most abundant group in Los Chiles (7971.4 µg/g of extract) aqueous extract, followed by Sarapiqui (6085.3–6464.1 µg/g of extract) in ethanolic and aqueous extracts, respectively. In contrast, extracts from Cat’s claw leaves showed a more uniform subclass distribution, for instance, all extracts are particularly rich in propelargonidin dimers (7904.3–14,390.8 µg/g of extract), followed by procyanidin dimers (3593.1–9988.8 µg/g of extract) and flavalignans-cinchonains (1074.6–7058.0 µg/g of extract).

In summary, this study ¹³⁾ shows that independently of the Cat’s claw plant origin, leaves extracts exhibit high contents of phenolic compounds and more importantly high contents of proanthocyanidins derivatives, mainly propelargonidin dimers and procyanidin dimers. These compounds are linked to diverse bioactivities, for instance due to their antioxidant capacity, as shown in reports for commercial dietary products from grape ¹⁴⁾ and cocoa ¹⁵⁾, which suggest these Cat’s claw (Uncaria tomentosa) extracts’ potential for further studies.

Table 1. Phenolic composition of aqueous extracts from Cat’s claw (Uncaria tomentosa) bark and leaves