What is bergamot

Bergamot orange (Citrus bergamia Risso et Poiteau), is a fragrant citrus fruit the size of an orange, with a yellow or green color similar to a lime, depending on ripeness. Bergamot is a plant belonging to the Rutaceae family, defined as a hybrid of bitter orange and lemon ¹⁾. Other authors ²⁾ considered bergamot a hybrid between a sour orange and lime (C. aurantifolia [Christm. and Panzer] Swingle). Bergamot an endemic plant of the Calabria region south of Italy – with more than 90% of the world production of bergamot comes from this region. However, small numbers of bergamot plants grow in other countries, such as Greece, Morocco, Iran and Ivory Coast, Argentina, and Brazil. Bergamot orange is primarily used for the extraction of its essential oil (bergamot essential oil).

Bergamot essential oil is a cold-pressed essential oil produced by cells inside the rind of a bergamot orange fruit. The scent of bergamot essential oil is similar to a sweet light orange peel oil with a floral note. Bergamot essential oil from the peel of this orange is used in perfume, to get rid of insects, in cosmetics, food, confectionery industries and to flavor tea ³⁾. Bergamot oil is also used in aromatherapy for depression, anxiety and poor digestion. Several clinical studies on aromatherapy with bergamot essential oil, in combination with other essential oils, have shown promising results: anxiety and stress reduction, anti‐depression, pain relief, and blood pressure and heart rate reduction. Further human studies with bergamot essential oil inhalation alone have also shown significant effects on anxiety reduction ⁴⁾, depression reduction ⁵⁾ and blood pressure ⁶⁾ and heart rate reduction ⁷⁾. In addition, bergamot essential oil has minimal side effects, if any ⁸⁾, suggesting bergamot essential oil inhalation may have potential therapeutic benefits including improving overall mental health and anxiety.

Bergamot juice, obtained from the endocarp after essential oils extraction, has long time been considered just a secondary and discarded product of the essential oil industry due to its bitter taste. Recently, bergamot juice gained attention because of its hypolipemic and hypoglycaemic activity ⁹⁾, as well as its anti-inflammatory ¹⁰⁾ and anti-cancer properties ¹¹⁾.

Figure 1. Bergamot orange

Bergamot essential oil

Bergamot essential oil is a greenish or brownish-yellow volatile oil (corresponding to the beginning and the end of the productive season) with a bitter aromatic taste and a characteristic pleasant odor.

The chemical composition of bergamot essential oil has been widely investigated and is well known ¹²⁾. Bergamot essential oil contains several bioactive molecules with potential health benefits. It is composed of both a volatile (93–96% of total) and a non-volatile (4–7% of total) fraction. The first is mainly represented by monoterpene and sesquiterpene hydrocarbons, and their oxygenated derivatives, along with aliphatic aldehydes, alcohols, and esters ¹³⁾. They include monoterpene limonene (25–53%) and high quantities of oxygenated compounds, such as linalool (2–20%), linalyl acetate (15–40%), γ-terpinene, and β-pinene ¹⁴⁾. The non-volatile fraction (4–7% of total) contains pigments, waxes, coumarins, and psoralens (such as 5-methoxypsoralen, also known as bergapten or 5-MOP, contained in about 0.2%), as well as bergamottine [5-geranyloxypsoralen]) ¹⁵⁾. Due to the well-known 5-MOP-induced photo-toxicity, a furocoumarins-free essential oil has been prepared for perfumery and cosmetic uses. The vacuum distillation of bergamot peels provides a high-quality bergamot essential oil totally devoid of 5-MOP that is chemically comparable to that of the cold-pressed oil ¹⁶⁾.

The characteristic flavor of Citrus oils is mainly provided by linalool, citral, and linalyl acetate ¹⁷⁾, whereas limonene and pinene are not much flavoring and they are relatively unstable compounds when exposed to heat and light. Thus, it is necessary to remove them to increase the shelf life of the products ¹⁸⁾.

Bergamot essential oil uses

Bergamot essential oil is one of the main basic constituents for the manufacture of perfumes, due to its ability to fix the aromatic bouquet of aromas and harmonize all of the essences, enhancing the fragrance. Bergamot essential oil is also used by the pharmaceutical industry, both to absorb the unpleasant smells of medicinal products and for its antiseptic and antibacterial properties. Finally, bergamot essential oil is used in the food and confectionery industries as a flavoring.

In Italian folk medicine, it has been used primarily for fever and parasitic diseases, in addition to mouth, skin, respiratory and urinary tract infections, gonococcal infections, leucorrhoea, vaginal pruritus, tonsillitis, and sore throats ¹⁹⁾. For its antiseptic and antibacterial proprieties, bergamot essential oil has been used as an antimicrobial agent to facilitate wound healing and has been included in preparations used to treat upper respiratory-tract disorders and hyperhidrosis. Moreover, bergamot essential oil’s use in magisterial, handcrafted, and homemade medicaments that were useful for skin disinfection, as well as use as an aid for healing minor wounds, has a long tradition in Italy. Currently, a furocoumarins-free bergamot essential oil is used in preparations for cutaneous use.

Bergamot essential oil is widely employed in aromatherapy, and has recently received renewed popularity in improving mood and mild symptoms of stress-induced disorders ²⁰⁾ and facilitating sleep induction ²¹⁾. Aromatherapy massage has been shown to relieve symptoms of anxiety in patients with cancer ²²⁾.

Bergamot essential oil aromatherapy

The scientific rationale of essential oils use in aromatherapy to improve mood and the mild symptoms of stress disorders, such as anxiety, depression, and chronic pain, is supported by both the physiological and psychological effects caused by the inhalation of volatile components that are believed to act via limbic system structures, such as the hippocampal formation, the hypothalamus and the pyriform cortex ²³⁾. Indeed, several clinical and experimental data indicate that aromatherapy can improve mood, alertness, and cognition. Specific EEG (electroencephalogram) changes associated with alertness and relaxation have been observed in some studies using essential oils. With regard to bergamot essential oil, these effects have been attributed to volatile components other than 5-MOP ²⁴⁾. Although the mechanisms by which bergamot essential oil induces its effects on the central nervous system have not yet been fully understood, it has been suggested that they could be mediated by the release of amino acids that interact with mechanisms that modulate synaptic plasticity.

Clinical research focused essentially on the therapeutic application of bergamot essential oil in aromatherapy, by inhalation or hand massage, on anxiety and stress responses. We reviewed the results of ten clinical studies in which only two reported negative results. Their principal data are reported in Table 1. Four studies evaluated the effects of different essential oil combinations, with bergamot essential oil being a constituent of the mixture associated with lavender (Lavandula angustifolia), cedarwood (Cedrus atlantica), ylang ylang (Cananga odorata) or frankincense ²⁵⁾. Among the studies with combinations, only Graham et al.’s (2003) study reported negative results. The other three studies showed positive effects based on the subjective responses to stress. The remaining six studies were all conducted using only bergamot essential oil. Five of these studies reported beneficial effects from bergamot essential oil, such as reduced heart rate, blood pressure and stress responses ²⁶⁾. One study investigating the effects of aromatherapy with bergamot essential oil on pain and nausea of children and adolescents undergoing stem cell transplantation, showed no benefit. Unfortunately, most of clinical trials did not report the quality parameters of the essential oils used. Even though these studies are not always satisfactory from a methodological point of view, they show that employment of bergamot essential oil in aromatherapy can be useful for reducing anxiety and stress responses, and it deserves further clinical investigation.

Table 1. Clinical studies on aromatherapy with bergamot essential oil (BEO), alone or in combination with other essential oils (lavender, cedarwood, ylang ylang, frankincense)

Antimicrobial Activity

It has been reported that bergamot essential oil has both antibacterial and antifungal activity against Campylobacter jejuni, Escherichia coli O157, Listeria monocytogenes, Bacillus cereus, and Staphylococcus aureus and dermatophytes, respectively ³⁸⁾. The in vitro activity of bergamot essential oil against Candida species suggests bergamot essential oil’s potential role in the topical treatment of Candida infections ³⁹⁾. Bergamot essential oil is also active against dermatophytes in vitro ⁴⁰⁾. Additionally, chitosan-based films containing bergamot essential oil at 0.5, 1, 2, and 3% w/w showed a significant dose-dependent inhibitory effect on the growth of Penicillium italicum ⁴¹⁾. Moreover, the in vitro effectiveness of the oil and vapors of bergamot and its components against common foodborne pathogens has been also investigated, and linalool was revealed to be the most effective anti-bacterial component ⁴²⁾.

Anti-inflammatory activity

Bergamot essential oil anti-inflammatory activity was demonstrated using the carrageenan-induced rat paw oedema test. The highest level of bergamot essential oil anti-inflammatory activity was obtained with a 0.10 ml/kg dosage. The median effective dose of bergamot essential oil was found to be 0.079 ml/kg ⁴³⁾.

Antiproliferative Activity

Bergamot essential oil has also been found to inhibit the survival and proliferation of SH-SY5Y neuroblastoma cells, ⁴⁴⁾ through the activation of multiple pathways leading to both necrotic and apoptotic cell death ⁴⁵⁾. Moreover, Russo et al. ⁴⁶⁾ showed that association of limonene and linalyl acetate, but not the exposure to the single compounds, caused significant cytotoxicity, suggesting for a major role of the combined action of these monoterpenes in cancer cell death induced by bergamot essential oil.

Neuroprotective Activities

Anxiolytic effects of bergamot essential oil (1.0, 2.5, and 5.0% w/w) were studied by administering it to rats subjected to anxiety-related behaviors, the elevated plus-maze and the hole-board tests, and then measuring the stress-induced levels of plasma corticosterone in comparison with the effects of diazepam. Bergamot essential oil (2.5%) and diazepam exhibited anxiolytic-like effects and attenuated the corticosterone response to acute stress ⁴⁷⁾.

After perfusion into the hippocampus via the dialysis probe (20 μl/20 min), bergamot essential oil produced a dose-dependent and Ca2+-independent increase of extracellular aspartate, glycine, taurine, GABA, and glutamate ⁴⁸⁾. Moreover, bergamot essential oil (0.5 ml/kg) given intraperitoneally 1 h before experimental occlusion of the middle cerebral artery, significantly reduced infarct size after 24 h, especially in the medial striatum and the motor cortex, as revealed by 2,3,5-triphenyl-2H-tetrazolium chloride staining of tissue slices ⁴⁹⁾.

Finally, in the human SH-SY5Y neuroblastoma cell line exposed to N-methyl-D-aspartate (NMDA), bergamot essential oil (0.0005–0.01%) reduced the death of SH-SY5Y cells caused by 1 mM NMDA in a concentration dependent manner. In addition, 0.01% bergamot essential oil counteracted the deactivation of Akt (a serine/threonine-specific protein kinase) and the consequent activation of glycogen synthase kinase 3 beta (GSK-3B) induced by NMDA. Results obtained with specific fractions of bergamot essential oil, suggested that monoterpene hydrocarbons could be important for neuroprotection ⁵⁰⁾.

Analgesic Effects

Capsaicin-induced nociceptive responses in the plantar surface of the hindpaw were significantly reduced by intraplantar injection of bergamot essential oil. Further experiments addressed the importance of linalool in bergamot essential oil oil-induced antinociception ⁵¹⁾. In another study, injection into the hindpaw of both the linalool and linalyl acetate compounds showed a significant reduction of nociceptive responses, which was much more potent than that induced by bergamot essential oil. The enhanced effect of the association of bergamot essential oil or linalool with morphine was antagonized by pretreatment with the opioid antagonist naloxone ⁵²⁾. The analgesic effect was also investigated using intraplantar injection of bergamot essential oil or linalool in mice with neuropathic hypersensitivity induced by partial sciatic nerve ligation. The results suggested that both bergamot essential oil and linalool reduced partial sciatic nerve ligation-induced mechanical allodynia in a dose-dependent manner through a local effect. Moreover, the analgesic effect was associated with a reduction of spinal extracellular signal-regulated protein kinase activation ⁵³⁾.

Cardiovascular Properties

Bergamottine significantly decreased the electrocardiographic changes that are typical of coronary arterial spasms and the occurrence of experimental cardiac arrhythmias provoked by pitressin in guinea pigs. Bergamottine also increased the dose of ouabain required to cause ventricular premature beats, ventricular tachyarrhythmias, and death. These results indicate that bergamottine possesses potential antianginal and antiarrhythmic properties ⁵⁴⁾.

It is known that lectin-like oxyLDL receptor-1 (LOX-1) is involved in smooth muscle cell proliferation and neo-intima formation occurring in injured blood vessels. Interestingly, in an experimental model of rat angioplasty, pretreatment with the non-volatile fraction of bergamot essential oil, reduced the neointima proliferation in a dose-dependent manner, together with free radical formation and LOX-1 expression ⁵⁵⁾. Moreover, it has been suggested that bergamot essential oil induces vasorelaxation of the mouse aorta by activating K+ channels and inhibiting Ca2+ influx ⁵⁶⁾, which differentially modulates intracellular Ca2+ levels in vascular endothelial and smooth muscle cells ⁵⁷⁾. These findings indicate that bergamot essential oil could be further studied for its potential role as a vasodilator agent in cardiovascular diseases.

Bergamot Essential Oil Side Effects

Bergamot essential oil is a widely used aromatic ingredient in cosmetics that may be applied on sun-exposed skin areas, although components such as bergapten, citropten, bergamotene, and other furocoumarins may cause phototoxic effects ⁵⁸⁾. There are only a few reports of phototoxic reactions caused by aromatherapy with bergamot essential oil. Freund, in 1916, was the first to describe a series of four cases of intense pigmentation in irregular areas after the use of Eau de Cologne before exposure to sunshine. He observed the same phenomenon after experimental use of bergamot essential oil, one of the constituents of Eau de Cologne. Rosenthal first used the term “Berloque dermatitis” because of the form of the resulting pigmentation ⁵⁹⁾. Hyperpigmentation of the neck, face, arms, or trunk that have been exposed to light has been attributed to psoralens in the bergamot essential oil. Cases have become much more rare since the introduction of psoralen-free bergamot essential oil.

Bergamot essential oil rich in 5-MOP has been used as sun tanning products for many years. In 1995, this use was banned and limited to the treatment of certain skin disorders. Toxic reactions can occur due to psoralen or UVA overdosing or due to accidental exposure to additional UVA, including sunlight exposure. Skin application of psoralens is more likely to induce photosensitivity reactions. To avoid the phototoxic and photocarcinogenic harm, the International Fragrance Association recommended that products that are applied in areas of skin exposed to the sun not have to contain more than 0.4% of bergamot essential oil. The occurrence of second-degree skin burns was found in two women after PUVA exposure ⁶⁰⁾.

The cases of the two patients were described as having localized and disseminated bullous phototoxic skin reactions that developed 48–72 h after ultraviolet exposure subsequent to aromatherapy with bergamot essential oil. The first case was of a woman that had used a bergamot aromatherapy oil preparation 3 days earlier and subsequently stayed exposed to the sun for several hours. In the second case, the woman visited a sauna 2 days before, where she was exposed to aromatherapy with bergamot essential oil before being exposed to UVA radiation while tanning. Cutaneous lesions developed gradually within 48–72 h. In both cases, the patients did not use other creams and/or medications at the same time ⁶¹⁾.

In another case, a 44-year-old man drank up to 4 L of black tea every day for 25 years. When he changed his brand because of occasional gastric pain, he began to drink the same daily quantity of Earl Gray tea. One week after the change, he noticed repeated muscle cramps. After 5 weeks of drinking the tea, the muscle cramps continued. Occasionally, he observed fasciculations, distal paraesthesia, and feelings of pressure in his eyes that were associated with blurred vision. Neurological examination confirmed reduced visual acuity and fasciculations. After 5 months, suspecting a relation between his symptoms and his tea intake, he stopped drinking Earl Gray, going back to black tea. Within 1 week, the symptoms completely disappeared. Successively, he observed that the symptoms did not appear if he ingested no more than 1 L of Earl Gray tea each day. Earl Gray tea is composed of black tea and bergamot essential oil. The adverse effects of bergamot essential oil in this patient could be explained by the potential effects of bergapten as a selective axolemmal potassium channel blocker, reducing potassium permeability at the nodes of Ranvier in a time-dependent manner. This may provoke hyperexcitability of the axonal membrane and phase alterations of potassium currents, producing fasciculation and muscle cramps. Impairment of the potassium channel function plays a pathogenic role in other disorders characterized by the occurrence of fasciculation. Prolonged opening of voltage-gated sodium channels caused by bergapten may enhance neuronal hyperexcitability ⁶²⁾.

Summary

Bergamot essential oil is generally well tolerated, but it possesses photosensitive properties because of the presence of furocoumarins, especially 5-MOP. Therefore, in topical preparations, psoralen-free essential oil was used in recent decades. As a consequence of this and because of safety concerns related to furocoumarins, the use of high quality controlled psoralen-free bergamot essential oil is recommended as a general precaution. However, although bergamot essential oil has been used extensively for many years, there have only been a few reports of phototoxic reactions to bergamot essential oil aromatherapy oil.

What is myrrh essential oil

Myrrh is an oleo-gum-resin made from dried tree sap derived from the stem of different Commiphora molmol (family Burseraceae) which is native to Northeast Africa and the Middle East ¹⁾. The name myrrh is derived from the Arabic and Hebrew word mur, which means bitter. It is a reddish brown mass, covered with a brownish yellow dust. Myrrh has a bitter and acrid taste and a balsamic odor ²⁾. With water myrrh forms an emulsion ³⁾. Different species of myrrh have also been found in different countries. Myrrh contains volatile oil, resin, and gum ⁴⁾. Sesquiterpenoids, nonsteroidal compounds found in myrrh, possess diverse biological functions, including antibacterial, anesthetic, and anti-hyperglycemic activity ⁵⁾. Recent studies have shown that sesquiterpenoids may be anti-tumorigenic ⁶⁾, ⁷⁾, but the molecular mode of action remains unknown. It is one of the most widely used plants in traditional medicine as an effective analgesic, antipyretic, antibacterial, and antifungal ⁸⁾. It has fasciolocidal, schistosomicidal, insecticidal, molluscicidal activities, and a potent activity against both intestinal and muscular stages of Trichinella spiralis ⁹⁾.

Figure 1. Myrrh oil resin

Myrrh and frankincense have been used for medical purposes in China and India for thousands of years ¹⁰⁾. In traditional Chinese medicine, frankincense and myrrh have synergistic effects when used in combination (generally in a 1:1 ratio), and the book Compendium of Materia Medica introduced the therapeutic characteristics of the combination of frankincense and myrrh during the Ming Dynasty. Modern pharmacological research has revealed that essential oils are the primary effective components in frankincense and myrrh oil that exhibit a broad spectrum of biological activities such as antimicrobial, anti-inflammatory, and antitumor activities ¹¹⁾.

Myrrh has been combined with gum resins in the anti-tumor prescription drug Xihuang wan (or Xihuang pill) for the treatment of cancer in China ¹²⁾, ¹³⁾.

Myrrh essential oil

Myrrh contains a 2-8% volatile oil (myrrhol), 23-40% resin (myrrhin), 40-60% gum, and a bitter principle 10-25% ¹⁴⁾.

The constituents of essential oil in two kinds of myrrh were analyzed by GC/MS and identified with their percent contents ¹⁵⁾. Myrrh essential oil contains cadinene, elemol, eugenol, cuminaldehyde, numerous furanosesquiterpenes including furanogermacranes, furanodiene, furanodienone, curzerenone, lindestrene as well as furanoeudesma-1,3-diene ¹⁶⁾.

Myrrh essential oil uses

Commiphora molmol is the most important species of myrrh which has been used as an effective antimicrobial agent, it is one of the most effective herbal medicines in the world for sore throats, canker sores and gingivitis ¹⁹⁾. It is useful for the treatment of acne, boils and arthritis ²⁰⁾. Myrrh has local stimulant and antihealing, antiseptic properties for wounds and abrasions. It is used as a mouth wash and as a uterine stimulant and emmenagogue ²¹⁾. It is used in the treatment of infections in the mouth as mouth ulcers, pyorrhea as well as catarrhal problems of pharyngitis and sinusitis ²²⁾. It is excellent in sore mouth and  extreme ulceration of mercurial ptyalism.

The extract of myrrh (gum) effectively decreases the absolute increment of blood glucose above the fasting concentration at all times of the oral glucose tolerance test in both normal and diabetic rats ²³⁾ and may prove to be a useful therapeutic agent in the treatment of non-insulin dependent diabetes mellitus ²⁴⁾. It is used also in cosmetic preparations for treatment of hair and scalp ²⁵⁾. Tincture of myrrh is used for the therapy of apthous ulcers (Stomatitis aphthosa) ²⁶⁾. Myrrh reduces cholesterol and triglycerides ²⁷⁾ and may terminate pregnancy ²⁸⁾. It exhibits strong antithrombotic activity ²⁹⁾. Extract of myrrh is used as digestive aid drug, and it is approved by the FDA for the use in food and oral health care drug products ³⁰⁾, ³¹⁾, ³²⁾.

Myrrh is used in traditional Chinese medicine to relieve pain and swelling due to traumatic injury ³³⁾. It is used as a hypolipidaemic agent ³⁴⁾. Myrrh is useful in chronic gastritis and atomic dyspepsia with full pale tongue and membrane, as well as frequent mucous stouts accompanied by flatulence ³⁵⁾. It helps in the treatment laryngitis and respiratory complains.

The petroleum ether extract of myrrh from Commiphora molmol produced significant inhibition of carrageenan-induced inflammation and cotton pellet granuloma. It also showed significant antipyretic activity in mice ³⁶⁾. Recently the cytotoxic and antitumor activity of myrrh has proved to be equivalent to those of the standard cytotoxic drug cyclophosphamide ³⁷⁾. Thus treatment with myrrh (250 and 500 mg/kg/day) was found to be cytotoxic in Ehrlich carcinoma tumor cells in mice ³⁸⁾. The Commiphora molmol treatment (125–500 mg/kg) showed no mutagenicity. It caused a highly significant and dose-dependent mitodepressant effect in the femoral cells as well as reduction of RNA levels in hepatic cells as compared with the control (cyclophosphamide) ³⁹⁾. Myrrh from Commiphora molmol pretreatment, at doses of 250-1000 mg/kg, provided dose dependent protection against the ulcerogenic effect of different necrotizing agent used ⁴⁰⁾. It also offered protection against mucosal damage caused by indomethacin ⁴¹⁾.

Treatment with the essential oil of myrrh significantly improved childhood atopic eczema. This may be due to a strong allergic contact dermatitis possibly provoked by the essential oils themselves ⁴²⁾.

The sesquiterpene fractions from Commiphora molmol, in particular furanodien-6-one and methoxyfuranoguaia-9-en-8-one, showed antibacterial and antifungal activity against standard pathogenic strains of Escherichia coli, Staphylococcus aureus and Pseudomonas aeruginosa, with minimum inhibitory concentrations ranging from 0.18 to 2.80 mg/ml. These compounds also have local anaesthetic activity blocking the inward sodium current of excitable mammalian membranes ⁴³⁾.

The botanical extract of myrrh could be used alone or in combination with sublethal doses of certain insecticides to control the cotton leafworm ⁴⁴⁾.

Histological examination of mosquito larvae treated with myrrh showed significant pathological effects on their fat, muscles, gut and nervous tissues ⁴⁵⁾.

Recently, a purified myrrh extract from methyl alcohol has been formulated as soft gelatin capsules, suppositories and emulsion known commerically as Mirazid which is considered a new safe antibilharzial drug with potential effects against Schistosoma mansoni and Schistosoma haematopium ⁴⁶⁾. In addition it is a potent fasciolicidal drug with a success rate of 94.1% ⁴⁷⁾.

Evaluation of the molluscicidal activity of mrryh from C. molmol on Biommphalaria alexandrina snails was studied, and it was proved that the activity is due to the oil extract rather than to the oleo resin ⁴⁸⁾. Fractionation of the oil extract led to the isolation of a bioactive component with molluscicidal activity (LC50 4.45 and 3.55 ppm) against the snails for exposure periods of 24 and 48 h, respectively ⁴⁹⁾.

The petroleum ether extract of myrrh from Commiphora mukul “guggul gum” decreased serum cholesterol, phospholipids, triglycerides and lipids in experimental hypercholesterolemic chicken, while ethyl acetate extract had less anticholesterolemic activity in rats ⁵⁰⁾, and it was effective as an hypolipidemic agent in dogs and monkeys ⁵¹⁾. It was also used in the treatment of rheumatoid arthritis and obesity ⁵²⁾. The steroid which was isolated from Commiphora mukul showed anti-inflammatory activity ⁵³⁾. It showed a marked inhibition of ADP, adrenaline and serotonin induced platelet aggregation ⁵⁴⁾. It also showed a strong thyroid stimulatory action when administered to albino rats ⁵⁵⁾. It is used as expectorant, antispasmodic, uterine stimulant and emmenagogue (increases menstrual flow). It is successfully used in chronic bronchitis, bronchial asthma, and pulmonary tuberculosis, and also in amenorrhoea (an abnormal absence of menstruation) and menorrhagia (abnormally heavy bleeding at menstruation) to regulate menses ⁵⁶⁾. The ethyl acetate extract of myrrh from Commiphora mukul, in albino rats, significantly prevented a rise in serum cholesterol and serum triglyceride levels caused by atherogenic diet ⁵⁷⁾. The essential oil was found to be fungistatic or fungicidal to some ubiquitous molds, depending on the concentration ⁵⁸⁾. The resin of Commiphora guidotti is widely used in treatment of stomach complains, wounds and diarrhoea in Somalia ⁵⁹⁾. T-Cadinol, the pharmacologically active sesquiterpene of scented Commiphora guidotti was shown to have a dose dependent smooth muscle relaxing effect on the isolated guinea pig ileum and a similar inhibitory effect on cholera toxin-induced intestinal hypersecretion in mice ⁶⁰⁾. It caused bacterial lysis and subsequent fatal loss of intracellular components in Staphylococcus aureus ⁶¹⁾. The resinous exudate from Commiphora abyssinica is sometimes applied as a plaster and used for spasms and fever ⁶²⁾. The washed bark, mixed with salt, is applied to snake-bites and the plant has been used as a stomachic (promoting the appetite or assisting digestion) and eye remedy.

Commiphora abyssinica extract exhibited a potent cytotoxic activity against KA31T cell line (10 mg/ml). The IC50 of this extract was 100 mg/ml against NIH3T3 cell line ⁶³⁾. The aqueous extract of the resin of Commiphora incisa significantly inhibited both the maximal edema response and the total edema response during 6 h of carrageenan-induced rat paw edema ⁶⁴⁾. The resin of Commiphora rostrata was found to be effective against predators and fungal pathogens ⁶⁵⁾. The bark and resin of Commiphora gileadensis are used as a cosmetic, soothing agent and to treat dog bites ⁶⁶⁾. The guggulipid of Commiphora wightii was shown to have hypocholesterolemic, antiseptic, anti-pathogenic, antiparasitic properties, and helps against non-specific diarrhoea and dysentery ⁶⁷⁾.

What is cedarwood essential oil

Cedarwood oil, is an essential oil derived from various types of conifers, most in the pine or cypress botanical families. In the US, cedarwood oil is produced from the foliage, and sometimes the wood, roots, and stumps of Juniperus virginiana trees, which have been left after cutting of trees for timber extraction ¹⁾. Although termed cedarwood oils, the most important oils of this group are produced from distilling wood of a number of different junipers/cypresses (Juniperus and Cupressus spp.), rather than true cedars (Cedrus spp.) ²⁾. Similar oils are distilled, pressed or chemically extracted in small quantities from wood, roots, and leaves from plants of the genera Platycladus, Cupressus, Taiwania, and Calocedrus.

Cedarwood oil alcohols and terpenes are listed as synthetic flavoring substances and adjuvants that are permitted by the United States Food and Drug Administration (21 CFR, § 172.515) for direct addition to food for human consumption. Cedarwood oil was registered as a pesticide in the United States in 1960. Currently, cedarwood oil is listed as a minimum risk pesticide and exempted from the Federal Insecticide, Fungicide, and Rodenticide Act regulations (40 CFR, § 152.25). Cedarwood oil is listed in the Toxic Substances Control Act Inventory ³⁾. However, no limits on recommended or permissible exposures are available.

Cedarwood oils can be extracted from several members of the Cupressaceae family, which encompasses true cedars, junipers, and cypresses. The three most prevalent cedarwood oil products in the United States are Virginia cedarwood oil (Juniperus virginiana), Texas cedarwood oil (Juniperus mexicana or Juniperus ashei), and Western red cedar (Thuja plicata) ⁴⁾. Western red cedar is the least commonly used of the three.

Cedarwood oil Synonyms ⁵⁾

• Cedar oil
• Cedarwood oil virginia
• Cedrus atlantica oil
• HSDB 1972
• Oil cedar
• Oil of cedar wood
• Oil of cedarwood
• Red cedarwood oil

Table 1. Plant sources of cedarwood oil

Note: Cupressus funebris is commonly stated to be the source of Chinese cedarwood oil but one Chinese source indicates that Juniperus chinensis, J. formosana and J. vulgaris are also used.

Most of the cedarwood oils are obtained from wild trees but little information is published on the extent to which oil production may have affected the natural resource. In Kenya, there has been a serious depletion of the wild trees as a result of over-exploitation for timber and oil. The position in China is not known. American oil production utilizes waste wood from trees felled for timber as well as the considerable areas where the junipers grow as invasive “weeds”.

Cedarwood oils each have characteristic woody odours which may change somewhat in the course of drying out. The crude oils are often yellowish or even darker in colour and some, such as Texas cedarwood oil, are quite viscous and deposit crystals on standing. They find use (sometimes after rectification) in a range of fragrance applications such as soap perfumes, household sprays, floor polishes and insecticides. Small quantities are used in microscope work as a clearing oil.

All the cedarwood oils of commerce contain a group of chemically related compounds, the relative proportions of these depending on the plant species from which the oil is obtained. These compounds include cedrol and cedrene, and while they contribute something to the odour of the whole oil they are also valuable to the chemical industry for conversion to other derivatives with fragrance applications. The oils are therefore used both directly and as sources of chemical isolates.

In India, Cedrus deodara oil has been shown to possess insecticidal and antifungal properties and to have some potential for control of fungal deterioration of spices during storage. However, its commercial use for this purpose remains, at present, speculation.

Excluding China, for which the magnitude of consumption of domestically produced cedarwood oil is not known, the United States, Western Europe and Japan are the major markets for the oil. After processing, the derivatives that are produced and their formulated products have a more diverse range of markets.

The USA utilizes much of its own Texas and Virginia cedarwood oils but also imports significant quantities of Chinese oil.

In Europe, demand for oil is mainly of the Chinese type.

Cedarwood oil chemical and physical properties

The most common components of cedarwood oils are sesquiterpene hydrocarbons and include cedrol, α-cedrene, cedrenol, cedral, cuparene, thujopsene, and widdrol, though the relative percentages can differ depending on the origin of the cedar trees ⁷⁾. The International Organization for Standardization set the following minimum and maximum standards for the components that make up the chromatographic profile of cedarwood oil (from Juniperus virginiana): α-cedrene (20% to 35%), β-cedrene (4% to 8%), thujopsene (10% to 25%), cuparene (1.5% to 7%), cedrol (16% to 25%), and widdrol (2% to 5%) ⁸⁾.

Cedarwood oil is a colorless to pale brown viscous liquid with a cedarwood odor and bitter taste. It is insoluble in water but soluble in ethanol or ether and may solidify at room temperature.

Virginia cedarwood oil is extracted from Juniperus virginiana trees by steam distillation. Cedarwood oil of unspecified origin is used commonly in fragrance formulations, and production for this purpose exceeds 100,000 pounds per year. Several cedarwood oil components can be isolated and acetylated for use in fragrances. Of the chemical components that make up cedarwood oil, cedrene, thujopsene, and cedrol are commonly isolated and often acetylated in the production of fragrance materials such as cedryl acetate and cedryl methylether. These extracts can be found in many cosmetic products (i.e., perfumes, lotions) that may be applied to most parts of the body and may come into contact with the ocular and nasal mucosae. Frequent application of these products on a daily basis leads to long-term chronic exposure. The cosmetics industry no longer reports concentration of use values to the United States Food and Drug Administration. However, data submitted to the FDA indicated that the maximum use concentration ranges from the 1984 product formulation data for Juniper Extract and Juniper Tar in cosmetics were 0.1% to 1%, and 1% to 5%, respectively.

Cedarwood oil uses

Cedarwood oil is commonly found in fragrance formulations. Cedrene, thujopsene, and cedrol are cedarwood oil components that are commonly isolated and often acetylated in the production of fragrance materials such as cedryl acetate and cedryl methylether ⁹⁾. These extracts can be found in many cosmetic products (i.e., perfumes, lotions, soaps) that are often applied to most parts of the body, and may come into contact with the ocular and nasal mucosae. Frequent application of these products on a daily basis leads to long-term chronic dermal and inhalation exposure. In addition to its use as a fragrance ingredient, cedarwood oil alcohols and terpenes have been used as food additives for flavor enhancement or adjuvants and are considered by the United States Food and Drug Administration (FDA) to be generally safe as a food additive preservative ¹⁰⁾, ¹¹⁾. The use of cedarwood oil terpenes as food additives in 1987 was estimated to be 166,500 pounds ¹²⁾. Cedarwood oil is used as a pesticide in sunscreens, pet collars, and in animal bedding ¹³⁾. Cedarwood oil has also been investigated as a topical mosquito repellent as an alternative to DEET; however, it was found to be ineffective against the multiple mosquito species that were tested ¹⁴⁾. However, it was found to be effective with an average knock-down range of 20% to 80% when applied directly to mosquitoes, cockroaches, and houseflies ¹⁵⁾. Virginia cedarwood oil was also found to be effective as a barrier repellent to red imported fire ants and black-legged tick nymphs ¹⁶⁾. Additionally, it is used in blocks and as a liquid spray for repelling moths and mildew from clothing and fabrics ¹⁷⁾. In vitro, Japanese cedarwood oils have been found to have anti-fungal properties against Trichophyton rubrum through the inhibition of DNA polymerase ¹⁸⁾.

Cedarwood essential oil toxicity and side effects

Animal studies testing the potential for skin irritation and sensitivity following acute exposure to low concentrations of cedarwood oil have resulted in conflicting data ¹⁹⁾, ²⁰⁾. The majority of these studies did not find sensitization or irritancy, but a few have shown that in rabbits, topical application of full strength (undiluted) cedarwood oil for 24 hours resulted in moderate skin irritation ²¹⁾. In humans, several short-term studies (24 hours to 4 days) have shown limited skin irritation effects following topical application of cedarwood oil at concentrations ranging from 0.2% to 20% ²²⁾, ²³⁾, ²⁴⁾. Acetyl cedrene, a common constituent of cedarwood oil, was also reported to have limited toxicity when evaluated in human irritation tests at concentrations up to 30% ²⁵⁾.

Disposition studies in rats with α-cedrene, a component of cedarwood oil, resulted in slow absorption with a Tmax between 2.8 and 4.4 hours following oral gavage dosing ²⁶⁾. In female rats, Cmax and AUC values increased proportionally to the dose and α-cedrene was extensively distributed to tissues with tissue:plasma ratios greater than 1 for all tissues; the highest ratio was present in lipid ²⁷⁾. The oral LD50 (lethal dose sufficient to kill 50 percent of a population of animals usually within a certain time, also called median lethal dose) value for cedarwood oil is greater than 5 g/kg body weight in rats, and the dermal LD50 (lethal dose sufficient to kill 50 percent of a population of animals usually within a certain time, also called median lethal dose) in rabbits is also greater than 5 g/kg ²⁸⁾.

Due to the widespread and increasing human exposure to cedarwood oil and lack of overall toxicological information, the National Cancer Institute nominated cedarwood oil for toxicity studies by the National Toxicology Program ²⁹⁾, ³⁰⁾. To address the lack of toxicological information following cedarwood oil exposure, 3-month dermal studies in male and female F344/N rats and B6C3F1/N mice were conducted. The concentrations used in these studies resulted in extensive skin lesions with no No-Observed-Effect-Level (NOEL) achieved in either the mice or the rats ³¹⁾. Benchmark dose modeling was performed to put these skin lesions, in addition to the final mean body weights, into perspective for risk assessment applications. However, due to the maximum effect level achieved for skin lesions in the mice at the lowest applied concentration, benchmark dose modeling of the skin lesions could only be performed in the rats. Groups of 10 male and 10 female mice and rats were administered 0% (untreated control), 0% (vehicle control), 6.25%, 12.5%, 25%, 50%, or 100% cedarwood oil in 95% ethanol by dermal application for 13 weeks ³²⁾. All of the rats survived until the end of the study, with the exception of two males in the 100% group that were euthanized due to severe skin lesions. All of the male and female mice in the 100% group were euthanized at week 10 of exposure as a result of the severity of skin lesions at the site of application. This was followed by euthanasia of one male and one female in the 50% group in week 11 and one male in the 12.5% group in week 12. All other male and female mice survived until the end of the study. In both rats and mice, treatment related clinical observations in the skin at the site of application included dermal irritation, thickened skin, and ulceration. These findings were noted in most of the male rats at applied concentrations of 25% or more, in most of the female rats at applied concentrations of 12.5% or more, and in the majority of the mice at all applied concentrations. Skin lesions were first noted on day 8 of cedarwood oil application in both rats and mice in the highest dose group. Treatment-related gross lesions were observed mainly in the skin at the site of application in the majority of the rats and mice, and included irritation, thickened skin, and ulceration ³³⁾. The time to first incidence decreased, while incidence and severity of epidermal ulcers increased with increasing dose in male and female rats and mice. Ulcerations presented earlier and were more severe in both sexes of the mice at all the doses tested (6.25% and above) ³⁴⁾ when compared to rats, where ulcerations were noted in both sexes at doses of 12.5% and greater, albeit with lower incidences and severities than what was seen in the mice ³⁵⁾.

In direct response to the inflammation and ulcerations at the site of cedarwood oil application, there were also histopathological changes in the hematopoietic system (bone marrow, spleen, and regional lymph nodes) that was most prominent in mice ³⁶⁾. The increased occurrences of these hematopoietic system lesions were considered to be secondary to the lesions observed in the skin at the site of application. Increased liver and kidney weights and increased incidences of kidney non-neoplastic lesions were also observed following dermal cedarwood oil exposure. Exposure-related decreases in absolute and relative thymus weights of rats and mice were also seen, with the male mice also displaying thymocyte depletion in the cortex of the thymus. The thymus is the most sensitive of the lymphoid organs in response to stress ³⁷⁾ and the thymus effects observed in these studies are consistent with stress-related organ effects. These additional organ weight changes and lesions are discussed more extensively within the National Toxicology Program’s Toxicity Report for Cedarwood Oil discussion ³⁸⁾. However, these data indicate that in addition to the site of application, there was a systemic inflammatory response to the skin lesions and the kidney and liver could also be potential targets for topical cedarwood oil exposure.

The final mean body weights of the 100% male and female rats were significantly less than those of the respective control groups at the end of the study (13% and 10% less, respectively) ³⁹⁾. Additionally, the mean body weight gain of the male rats from the 25% group was significantly less than the vehicle control group. In the mice, the final mean body weights of the 25% and 50% male dose groups (10% and 14% less, respectively) and the 12.5%, 25%, and 50% female dose groups (12%, 19%, and 13% less, respectively) were significantly less than the vehicle control groups. This also corresponded to decreased mean body weight gains in comparison to the controls, in both the male and female mice at doses of 12.5% and above ⁴⁰⁾.

However, the Food and Drug Administration (FDA) no longer requires the cosmetics industry to report concentration of use values on cosmetic product labels; however, 1984 product formulation data indicate that the maximum use concentrations for Juniper extract and Juniper tar in cosmetics were 0.1 to 1% and 1 to 5%, respectively ⁴¹⁾. Although these reported data are not current, these levels appear to be consistent with products that have been identified as currently available on the market (e.g., an insect repellant product marketed as all natural that contains 1.5% cedarwood oil). Given the reported data and what is available on the market, the benchmark doses at the lower 95% confidence limits levels determined for cedarwood oil in the toxicological studies overlap with those that were permitted for use in cosmetics ⁴²⁾.

In conclusion, dermal application of cedarwood oil for three months resulted in exposure-related skin lesions in both sexes of rats and mice ⁴³⁾. Skin irritation resulted in a systemic inflammatory response that was mild in the rats in the higher dose groups and more pronounced in the mice in nearly all the dose groups, reflecting the increased severities of the skin lesions in the mice. Benchmark doses modeling of these skin lesions in the rats resulted in the lower benchmark doses at 95% confidence limits levels for cedarwood oil that overlap with previously reported use levels and indicate concern for human exposure. Sensitization is a key early event in the development of allergic contact dermatitis and is a parameter currently used in both hazard and risk assessments ⁴⁴⁾.

What is borage oil

Borage (Borago officinalis Linn), also known as a star flower, is an annual herb in the flowering plant family Boraginaceae ¹⁾. Borage is a medicinal plant which has different usages in pharmaceutical, industrial and forage fields and is used in production of drinks and salads. This plant is known as high plant in Mediterranean region. The leaves are edible and the plant is grown in gardens for that purpose in some parts of Europe. Vegetable use of borage is common in Germany (as an ingredient in green sauce, made in Frankfurt), Crete and in the Italian region of Liguria (to fill traditional ravioli pasta). Vegetable borage is also very popular in the cuisine of the Spanish regions of Aragon and Navarra (i.e., boiled and sautéed with garlic, served with potatoes). Borage is also used by naturopathic practitioners in the regulation of metabolism and the hormonal system, being considered a good remedy for premenstrual syndrome and menopause symptoms, such as hot flashes ²⁾. In Iran, people make tea (Gol Gav Zaban tea) to relieve colds, flu, bronchitis, rheumatoid arthritis, and kidney inflammation ³⁾.

The plant is also commercially cultivated for borage seed oil extracted from its seeds. cultivated for medicinal although it is commercially cultivated for borage seed oil. Borage seed oil is rich in gamma-linolenic acid (30%-40%) which is used as dietary or food supplement. Gamma-linolenic acid, a omega-6 polyunsaturated fatty acid, is sometimes prescribed as anti-inflammatory drug with this belief that it lacks some of the common side-effects of other anti-inflammatory drugs. Gamma-linolenic acid is also used for the treatment of multiple sclerosis, diabetes, heart diseases, arthritis, eczema, autoimmune disorders, cancer and premenstrual syndrome ⁴⁾. Gamma-linolenic acid is one of the volatile fatty acids which is synthesized just by a few plant varieties and often found in their seeds. The main sources of the gamma-linolenic acid are borage and evening primrose ⁵⁾. But borage is a better resource of the gamma-linolenic acid since its seeds contain 30%-40% oil of which 20%-30% is gamma-linolenic acid. This amount is approximately twice as many as that of in evening primrose. The oil of borage is more constant and its process is simpler than the oil of the evening primrose ⁶⁾.

Borage Leafs

The leaves of borage contains following compounds: a few amount of pyrrolizidine alkaloids, licosamin, intermedin, sopinin, sopindian, yezan, colin; fatty acids including alpha-linolenic acid [ALA] (55%) and gamma-linolenic acid (more than 4%); silicic acid (1.5%-22.0%); potassium, calcium, nitrate potassium (3%), acetic, lactic and malic acid; δ-bornesitol, cianozhens; fresh leaves also contain mucilage hydrolysable to glucose, galactose, arabinose and alantoein up to 30%; leaves of borage in seeding stage contain 2.5-5.0 mg gamma-linolenic acid and 5.7-9.0 mg stearidonic acid ⁷⁾. The most amount of the gama-linolenic fatty acids are seen in May or June and the most amount of that in upper leaves of the stem in August or September ⁸⁾.

Borage Seeds

Borage is important due to high amount of gamma-linolenic acid available in its seed oil. In a comprehensive research, antioxidants properties of borage extracts have been reported ⁹⁾. These antioxidants properties of borage are attributed to phenolic compounds. It has been determined that rosmarinic acid, synergic acid and synaptic acid are main phenolic compounds available in extract of borage seed. These three compounds act as bioactive molecules and exert antioxidant and anti-inflammatory properties ¹⁰⁾. Specially, rosmarinic acid is investigated and employed by the food and pharmaceutical industries ¹¹⁾. Rosmarinic acid is the main component of rosemary extract which is used extensively in food industries.

There is potential for borage antioxidants to be used in food formulations and in skin health products as compounds which absorb UV. It has been suggested that linoleic acid and palmitic acid are dominant fatty acids available in mature seeds of borage ¹²⁾. Borage oil due to high amount of gamma-linolenic acid is investigated by food and pharmaceutical research groups. Oils containing gamma-linolenic acid is used to treat some diseases resulted from lack of gamma-linolenic acid in human ¹³⁾.

Figure 1. Borage flower

Borage Oil Uses

Borage seeds oil is the richest plant source of γ-linolenic acid (gamma-linolenic acid) which is used as dietary supplement for prevention and/or treatment of various degenerative pathologic illnesses ¹⁴⁾, as osteoporosis ¹⁵⁾, diabetes ¹⁶⁾, and cancer ¹⁷⁾. Gamma-linolenic acid has also been reported to suppress tumor growth in vitro ¹⁸⁾, improve oxygenation status ¹⁹⁾, exert anti-inflammatory activity and display beneficial effects in the early stages of sepsis ²⁰⁾. Gamma linolenic acid is thought to exert its therapeutic effect in rheumatologic and dermatologic conditions by inhibiting leukotriene synthesis, resulting in anti-inflammatory and anti-thrombotic effects ²¹⁾.

Table 1. Fatty acids methyl esters composition of borage oil as a percentage concentrations of total fatty acids

Today gamma-linolenic acid and stearidonic acid supplements and oils containing these fatty acids are used in diet to meet the shortage of necessary fatty acids and prostaglandin. They are also used in folk medicine in treating thrombosis, inflammation and cancer ²³⁾. Atopic dermatitis is an inherited and regressive disease which is seen in 5%-10% of children and now local corticosteroid is often used to remove inflammatory and itchy rashes seen in patients. However a recent good quality systematic review ²⁴⁾ involving 27 studies, with 1596 adults and children from 12 countries, found no evidence that  orally taken either borage oil or evening primrose oil are effective in treatment of eczema (atopic dermatitis). Both of these products and the placebos used in the studies had similar mild, temporary side-effects, which were mainly headache and upset stomach or diarrhea ²⁵⁾. In conclusion, there is no convincing evidence of the benefit of dietary supplements in eczema, and they cannot be recommended for the public or for clinical practice at present.

In rheumatoid arthritis there is some evidence that oils containing gamma-linolenic acid (evening primrose, borage oil or blackcurrant seed oil) afford some benefit in relieving symptoms for rheumatoid arthritis ²⁶⁾. However. we are uncertain of the effects of other herbal therapies because only single studies were available, or important features of rheumatoid arthritis, such as changes in the number of swollen and tender joints, were not reported. Many trials of herbal therapies are hampered by research design flaws and inadequate reporting. Further investigation of each herbal therapy is warranted, particularly via well designed, fully powered, confirmatory clinical trials that use American College of Rheumatology improvement criteria to measure outcomes.

It has been reported that treatment of aged rats with gamma-linolenic acid restores the hippocampal long-term potentiation and reversed age-related changes in glutamate release ²⁷⁾ and improves both memory and N-methyl-D-aspartic acid receptor function ²⁸⁾, suggesting that at least part of its activity is specifically directed at synaptic plasticity. It is concluded that gamma-linolenic acid and the anti-oxidant alpha-lipoic acid, which is known to improve early deficits in peripheral nerve conduction in diabetic rats, is unable to reverse late deficits in the peripheral and central nervous system of streptozotocin-diabetic rats ²⁹⁾. Treatment with gamma-linolenic acid rich natural oils was previously shown to partially prevent nerve ischemia and associated conduction anomalies and improved long-term potentiation in the hippocampus in rats with experimental diabetes mellitus ³⁰⁾.

Borage oil side effects

Apart from the temporary headache, and upset stomach or diarrhea, borage oil has been reported to cause status epilepticus (continuous seizure activity) ³¹⁾. A case report of a 41 year old previously healthy female, who one week prior to presentation, began taking between 1,500 and 3,000 mg of borage oil a day. She was also regularly taking several other supplements including vitamin B and E complexes, ascorbylpalmitate, coenzyme Q10, and L-carnitine. She did not take any prescription medications and did not drink alcohol or use illicit drugs. Her seizures were controlled with pentobarbital but would reoccur as pentobarbital dosing was reduced. Levetiracetam was instituted. After roughly 10 days in the pentobarbital coma, the pentobarbital was tapered and her neurological status rapidly improved. The patient developed an increase in transaminases and the phenytoin was discontinued. She was transferred to a rehab facility. While at the rehab facility, she developed two brief seizures that resolved spontaneously. Carbamazepine was added and she had no further seizure activity. At 4-months follow-up, she reported no convulsive seizures but was occasionally having simple partial seizures which involved a familiar-sounding tone that can be triggered by loud noises. She also reported short-term memory and word-finding impairment. At that point, she transferred her care to a neurologist closer to her home and was lost to follow-up ³²⁾.

In a literature review of central nervous system (CNS) effects related to gamma-linolenic acid or linolenic acid, found only two reports describing a total of five cases of purported gamma-linolenic acid-induced seizures. Three patients with schizophrenia developed EEG-confirmed temporal lobe epilepsy after starting treatment with evening primrose oil. All patients improved after withdrawal of primrose oil and institution of carbamazepine treatment ³³⁾. Generalized tonic–clonic seizures were described in two further schizophrenic patients after starting treatment with evening primrose oil ³⁴⁾. However, one recent study has called these two earlier case series into question ³⁵⁾. It should be noted that all five cases used evening primrose oil rather than Borage oil, which was used by female patient discussed earlier. Borage oil may have the potential to lower the seizure threshold although some studies report anti-epileptic effects of fatty acids gamma-linolenic acid and linolenic acid ³⁶⁾. Research in this regard is mixed and so no certain conclusions can be drawn. These herbal preparations may best be avoided by epilepsy patients at least until this issue is clarified ³⁷⁾.

What are adaptogenic herbs

The term “adaptogen” was coined in the middle of the 20th century by the Russian scientist Lazarev ¹⁾ to describe medicinal plants or substances “that increase resistance to a broad spectrum of harmful factors (stressors) of different physical, chemical, and biological natures” ²⁾. “Adaptogen” an agent that allows an organism to adapt to unfavorable stressful conditions, which could be physical, chemical, biological, or mental conditions ³⁾. Adaptogens are considered “metabolic regulators, which increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors”⁴⁾. Inherent in Lazarev’s definition is the concept that administration of the adaptogenic agent allows an organism to pre-adapt itself in a manner that allows it to be more capable of responding appropriately when diverse demands are eventually placed on it. The mode of action of adaptogens is basically associated with the stress-system (neuroendocrine-immune complex) and can be directed on the various targets of the system involved in regulation (activation and inhibition) of stimulus-response coupling. Some pioneer researchers in this field put forth specific criteria that need to be fulfilled to qualify as an adaptogens, In 1969, Brekhman and Dardymov proposed specific criteria that need to be fulfilled in order for a substance to qualify as an adaptogen (see criteria below). Adaptogens could be synthetic or natural substances. However, most researches on adaptogens have focused on natural substances (specifically plants), and the term “phytoadaptogens” is now commonly used for adaptogens of plant origin ⁵⁾.

It is now accepted that true adaptogens must ⁶⁾:

1. Possess stress-protective effects (i.e. reduction of stress-induced damage) such as anti-fatigue, anti-infection and restorative activities;
2. Present stimulating effects, following both single and multiple administration, that give rise to an increase in working capacity and mental performance against a background of fatigue and stress (such stimulating effects must be different from those of conventional CNS [central nervous system] stimulants and anabolics that deplete energy and plastic resources of the organism and are accompanied by negative side effects including drug withdrawal syndrome); and
3. Be innocuous and not disturb the normal level of body functions, but rather present a normalizing influence on the pathologic state, independent of the nature of that state.

Subjecting animals and humans to a period of stress produces characteristic changes in several hormones and parameters associated with the central nervous system and the hypothalamic-pituitary-adrenal axis (HPA). Hypothalamic–pituitary–adrenal (HPA) axis changes include an increase in cortisol, a reduced sensitivity of the HPA to feedback down-regulation, and a disruption in the circadian rhythm of cortisol secretion. Central nervous system changes include the stress-induced depletion of catecholamine neurotransmitters such as norepinephrine and dopamine. An acute increase in beta-endorphin levels is also observed under stressful conditions.

To successfully combat stress and stressful situations, adaptation is required. Adaptation might be best thought of as the ability to be exposed to a stressor, while responding with either decreased or no characteristic hormonal perturbations. Adaptation also implies being prepared to and capable of rapidly reassuming homeostasis after the stressor is withdrawn. As an example, a well-trained athlete can participate in an event that would induce a large HPA perturbation (stress response) in a sedentary person, and yet the athlete will be relatively unaffected. This is a result of adaptation that has occurred during the athlete’s training process. Additionally, if athletes are exposed to stressors they were not trained for, hormonal perturbations characteristic of a stress response would be expected; however, this response might not be as great as that found in less fit individuals. Furthermore, after the stress ended, their physiology would be expected to re-establish homeostasis rapidly. This is a result of non-specific resistance to stress gained by virtue of a training-induced higher level of fitness.

The utility of plant adaptogens is analogous to the training an athlete undergoes in order to prepare for competition. Plant adaptogens cause our physiology to begin the adaptation process to stress. When a stressful situation occurs, consuming adaptogens generates a degree of generalized adaptation (or non-specific resistance) that allows our physiology to handle the stressful situation in a more resourceful manner.

Plant adaptogens are compounds that increase the ability of an organism to adapt to environmental factors and to avoid damage from such factors ⁷⁾. The beneficial effects of multi-dose administration of adaptogens are mainly associated with the hypothalamic–pituitary–adrenal (HPA) axis, a part of the stress-system that is believed to play a primary role in the reactions of the body to repeated stress and adaptation. In contrast, the single dose application of adaptogens is important in situations that require a rapid response to tension or to a stressful situation. In this case, the effects of the adaptogens are associated with another part of the stress-system, namely, the sympatho–adrenal-system (SAS), that provides a rapid response mechanism mainly to control the acute reaction of the organism to a stressor ⁸⁾.

It should be noted that only ⁹⁾:

• Schizandra chinensis,
• Eleutherococcus senticosus (Siberian ginseng) andRhodiola rosea (“Golden root” or “Arctic root”) have been found to be fully compliant with this specific definition of adaptogen.

A review ¹⁰⁾ on the effects of single doses of adaptogens derived from Rhodiola rosea, Schizandra chinensis and Eleutherococcus senticosus that focuses primarily on the sympatho–adrenal-system (SAS) found, single administration of these adaptogens effectively increases mental performance and physical working capacity in humans. Rhodiola rosea is the most active of the three plant adaptogens producing, within 30 min of administration, a stimulating effect that continues for at least 4–6 hours. The active principles of the three plants that exhibit single dose stimulating effects are glycosides of phenylpropane- and phenylethane-based phenolic compounds such as salidroside, rosavin, syringin and triandrin, the latter being the most active.

As an example of this process, Rhodiola rosea administration promotes a moderate increase in the amount of serum immunoreactive beta-endorphin in rats under basal conditions. This moderate increase is similar to that found when rats are adapted to exercise. When Rhodiola rosea-treated rats were subjected to a 4-hour period of non-specific stress, the expected elevation in beta-endorphin was either not observed or substantially decreased. Consequently, the characteristic perturbations of the HPA were decreased or totally prevented ¹¹⁾. In these rats administration of Rhodiola rosea appears to have generated non-specific resistance and prepared the rats to respond more appropriately to the eventual stressful situation.

The adaptogen concept

Resistance to stress and survival depends on adaptability and the thresholds that determine an organism’s innate tolerance to a given level of stress. The stress-induced responses of the innate and adaptive defense systems involve numerous mediators of stress signaling, including the neuroendocrine–immune complex that supports allostasis in simple and complex organisms ¹²⁾. Repeated mild exposure or low doses of stress result in the increased resistance of cells and organisms to subsequent stress exposure, resulting in an adaptation that favors survival. This phenomenon of adaptation to repetitive low-level stress was first described by Hans Selye in 1936 ¹³⁾ using rats exposed to low temperatures, low oxygen tension, muscular exercise, adrenaline, and morphine. Several nonspecific reactions were evoked (thymus atrophy, adrenal hyperplasia, stomach ulceration, increased secretion of cortisol and catecholamines, etc.), which Selye termed the general adaptation syndrome (GAS) ¹⁴⁾. GAS necessitates three stages. The first is the initial stress recognition or “alarm reaction” when symptoms emerge. The second stage involves the acquisition of nonspecific resistance, following which symptoms disappear. Stage 3 signals exhaustion, when the same symptoms reappear, followed by death.

What happens in your body during stress

Biochemical Changes

The responses to stressors may be pleasant or unpleasant, and they vary among people and even within the same person at different times.

Your body’s homeostatic mechanisms attempt to counteract stress. When they are successful, the internal environment remains within normal physiological limits. If stress is extreme, unusual, or long lasting, the normal mechanisms may not be enough. In 1936, Hans Selye, a pioneer in stress research, showed that a variety of stressful conditions or noxious agents elicit a similar sequence of bodily changes. These changes, called the stress response or general adaptation syndrome, are controlled mainly by the hypothalamus.

The stress response occurs in three stages:

1. Stage 1: an initial Fight-or-Flight Response,
2. Stage 2: a Slower Resistance reaction, and eventually
3. Stage 3: Exhaustion.

Research on the stress response has shown that many of the physiological alterations associated with stress are brought about by centrally controlled biochemical changes – stressors stimulate the hypothalamus to initiate the stress response through the fight-or-flight response and the resistance reaction. During situations perceived as being acutely stressful, the 2 main pathways activated are:

1. The Hypthothalamus-Pituitary-Adreno Axis and
   
2. The Sympatho-Adreno-Medullary Axis.

Both axes are activated by the hypothalamus secreting corticotrophin-releasing hormone (CRH), which causes the pituitary gland to release adrenocorticotropic hormone (ACTH). In the more rapidly acting of these pathways, the Sympatho-Adreno-Medullary axis, ACTH stimulates the adrenal medulla to release the catecholamines epinephrine and norepinephrine ¹⁵⁾. These stress-induced alterations are directly linked to a number of the physiological changes that take place in the body including increases in blood pressure, heart rate, respiration, and oxygen consumption. In the slower-acting HPA axis, blood-borne ACTH acts on the adrenal cortex to release cortisol. Once in the bloodstream, cortisol induces metabolic changes in the liver, resulting in increased glucose concentrations in blood and tissues. The increased glucose produces adenosine triphosphate (ATP) to repair damaged cells and enables metabolically active cells throughout the body to respond to the stressor ¹⁶⁾.

Figure 1. Hypthothalamus-Pituitary-Adreno Axis and Sympatho-Adreno-Medullary Axis

Note: Responses to stressors during the stress response. Red arrows (hormonal responses) and green arrows (neural responses) in (a) indicate immediate fight-or-flight reactions; black arrows in (b) indicate long-term resistance reactions.

The Fight-or-Flight Response (Stage 1 of Stress)

The fight-or-flight response, initiated by nerve impulses from the hypothalamus to the sympathetic division of the autonomic nervous system (ANS), including the adrenal medulla, quickly mobilizes the body’s resources for immediate physical activity (see Figure 1 above). It brings huge amounts of glucose and oxygen to the organs that are most active in warding off danger: the brain, which must become highly alert; the skeletal muscles, which may have to fight off an attacker or flee; and the heart, which must work vigorously to pump enough blood to the brain and muscles. During the fight-or-flight response, nonessential body functions such as digestive, urinary, and reproductive activities are inhibited. Reduction of blood flow to the kidneys promotes release of renin, which sets into motion the renin–angiotensin–aldosterone pathway. Aldosterone causes the kidneys to retain Na+, which leads to water retention and elevated blood pressure. Water retention also helps preserve body fluid volume in the case of severe bleeding.

The Resistance Reaction (Stage 2 of Stress)

The second stage in the stress response is the resistance reaction (Figure 1b). Unlike the short-lived fight-or-flight response, which is initiated by nerve impulses from the hypothalamus, the resistance reaction is initiated in large part by hypothalamic releasing hormones and is a longer-lasting response. The hormones involved are corticotropin-releasing hormone (CRH), growth hormone–releasing hormone (GHRH), and thyrotropin-releasing hormone (TRH).

Corticotropin-releasing hormone (CRH) stimulates the anterior pituitary to secrete adrenocorticotropic hormone (ACTH), which in turn stimulates the adrenal cortex to increase release of cortisol. Cortisol then stimulates gluconeogenesis by liver cells, breakdown of triglycerides into fatty acids (lipolysis), and catabolism of proteins into amino acids. Tissues throughout the body can use the resulting glucose, fatty acids, and amino acids to produce ATP (adenosine triphosphate is the energy packets necessary for cells to function) or to repair damaged cells. Cortisol also reduces inflammation.

A second hypothalamic releasing hormone, growth hormone–releasing hormone (GHRH), causes the anterior pituitary to secrete growth hormone (GH). Acting  via insulin like growth factors (ILGF), GH stimulates lipolysis and glycogenolysis, the breakdown of glycogen to glucose, in the liver. A third hypothalamic releasing hormone, thyrotropin-releasing hormone (TRH), stimulates the anterior pituitary to secrete thyroid-stimulating hormone (TSH). TSH promotes secretion of thyroid hormones, which stimulate the increased use of glucose for ATP production. The combined actions of GH and TSH supply additional ATP for metabolically active cells throughout the body.

The resistance stage helps the body continue fighting a stressor long after the fight-or-flight response dissipates. This is why your heart continues to pound for several minutes even after the stressor is removed. Generally, it is successful in seeing you through a stressful episode, and your bodies then return to normal. Occasionally, however, the resistance stage fails to combat the stressor, and the body moves into the state of exhaustion.

Stage of Exhaustion (Stage 3 of Stress)

The resources of the body may eventually become so depleted that they cannot sustain the resistance stage, and exhaustion ensues. Prolonged exposure to high levels of cortisol and other hormones involved in the resistance reaction causes wasting of muscle, suppression of the immune system, ulceration of the  gastrointestinal tract, and failure of pancreatic beta cells. In addition, pathological changes may occur because resistance reactions persist after the stressor has been removed.

This puts you at increased risk of numerous health problems, including:

• Anxiety
• Depression
• Digestive problems
• Headaches
• Heart disease
• Sleep problems
• Weight gain
• Memory and concentration impairment

That’s why it’s so important to learn healthy ways to cope with the stressors in your life.

Figure 2. Comparative Impact of the Acute Stress and Relaxation Responses

Note:

Central and Peripheral Nervous System Activities

Using blood pressure as an example, we show how acute stress and relaxation responses alter hypothalamus-pituitary-adrenal (HPA) and sympatho-adreno-medullary (SAM) axis activities. These responses introduce contrasting hormonal and signal molecule changes that in turn influence clinically significant conditions such as high blood pressure. Epi = epinephrine or adrenaline /  Ne = norepinephrine or noradrenaline / SAM axis is the adrenal medulla to Ne and Epi / Cort = cortisol / NO = nitric oxide / HPA axis is the adrenal cortex to Cort (cortisol)

Why you react to life stressors the way you do ?

Your reaction to a potentially stressful event is different from anyone else’s. How you react to stressors in your life is affected by such factors as:

• Genetics. The genes that control the stress response keep most people on a fairly even keel, only occasionally priming the body for fight or flight. Overactive or underactive stress responses may stem from slight differences in these genes.
• Life experiences. Strong stress reactions sometimes can be traced to traumatic events. People who were neglected or abused as children tend to be particularly vulnerable to stress. The same is true of people who have experienced violent crime, airplane crash survivors, military personnel, police officers and firefighters.

You may have some friends who seem laid-back about almost everything and others who react strongly at the slightest stress. Most reactions to life stressors fall somewhere between those extremes.

The adaptive stress response

The adaptive stress response occurs in a variety of regulatory systems from the cellular level to the whole organism. At the cellular and molecular levels, intra- and extracellular signaling pathways promote upregulation of antiapoptotic proteins, neuropeptides, and antioxidant enzymes in the alarm phase ¹⁷⁾. Figure 3 outlines seven adaptive stress response signaling pathways that protect neurons against degeneration and promote synaptic plasticity and depicts how adaptogens influence signaling to promote neuroplasticity and decrease vulnerability to neurodegeneration. In this context, botanical adaptogens are metabolic regulators that increase survival by increasing adaptability in stress.

A characteristic feature of adaptogens is that they act as eustressors (i.e., “good stressors”) and as mild stress mimetics or “stress vaccines” that induce stress-protective responses ¹⁸⁾. Mild (survivable) stress induces a resistance or “immunity” to subsequent, more severe stress exposure ¹⁹⁾. However, this stress-induced resistance carries no memory function, and repeated exposure to the adaptogen is required to maintain the plastic adaptive state. Another comparison could be made with repetitive physical exercise, which increases endurance and performance ²⁰⁾. A state of nonspecific resistance (SNSR) could be achieved either by the gradual “training” of an organism to withstand the effects of the stress or by adaptogens that mimic the stress. The repeated administration of adaptogens and the consequent adaptogenic or stress-protective response arise in a manner analogous to repeated physical exercise that leads to prolonged SNSR and increased endurance and stamina ²¹⁾. The phenomenon of adaptation to stress also underpins the hormetic response, which is defined as an adaptive response characterized by a biphasic dose–response, with a low dose that is stimulatory (i.e., has a beneficial effect) and a high dose that is inhibitory (i.e., has a toxic effect) ²²⁾.

Figure 3. Adaptive stress response and effects of adaptogens

Note: Adaptive cellular stress response signaling that mediates beneficial effects of environmental challenges and adaptogens on neuroplasticity and vulnerability to neurodegeneration. A typical glutamatergic neuron in the hippocampus is depicted receiving excitatory inputs (red) from neurons activated in response to exercise, cognitive challenges, and dietary energy restriction. Examples of seven different adaptive stress response signaling pathways that protect neurons against degeneration and promote synaptic plasticity are shown. During exercise and cognitive challenges, postsynaptic receptors for glutamate, serotonin, and acetylcholine are activated to engage intracellular signaling cascades and transcription factors that induce the expression of neuroprotective proteins, including brain-derived neurotrophic factor (BDNF), mitochondrial uncoupling proteins (UCPs), and antiapoptotic proteins (e.g., BCL-2). BDNF promotes neuronal growth, in part, by activating the mammalian target of rapamycin (mTOR). Mild cellular stress resulting from reduced energy substrates and reactive oxygen species (ROS) engages adaptive stress response pathways, including those that upregulate antioxidant enzymes (AOEs) and protein chaperones. Release of GABA from interneurons in response to activity in excitatory circuits (as occurs during exercise and cognitive challenges) hyperpolarizes excitatory neurons, protecting them from Ca2+ overload and excitotoxicity. CaMKII, calcium/calmodulin kinase II; CREB, cyclic AMP response element–binding protein; DAG, diacylglycerol; FOXO3, forkhead box protein O3; HO1, heme oxygenase 1; HSF1, heat shock factor 1; IP3 PKC, inositol-trisphosphate 3 protein kinase C; NF-κB, nuclear factor κB; NQO1, NAD(P)H-quinone oxidoreductase 1; NRF2, nuclear regulatory factor 2.

Pharmacology and the mechanism of action of adaptogens

The pharmacologic efficacy of adaptogens and their stress-protective effects are usually investigated by testing cognitive function and physical endurance under stressful conditions ²⁴⁾. Further, the use of valid and specific biomarkers related to pharmacological activity is a generally accepted practice in pharmacology.

Which effectors are responsible for mediating adaptogenic effects, and what are their key molecular targets ?

A number of human and animal studies have suggested that the stress hormones cortisol and neuropeptide Y (NPY) and several important mediators of the adaptive stress response (e.g., nitric oxide, stress-activated protein kinases, heat shock proteins (HSP70 and HSP25), and the FOXO (DAF-16) transcription factor) are key players in mediating the adaptogenic effects of plant extracts (e.g., Rhodiola, Eleutherococcus, Schisandra, ginseng, Bryonia, Withania, etc.) ²⁵⁾. These mediators orchestrate the process of stress adaptation (including aging or disease pathology), with no single contribution that can be estimated with any degree of certainty. Figures 4 show the hypothetical mechanisms of action of adaptogens in stress-induced fatigue, depression, and aging.

Several reviews describe the possible mechanisms of action of adaptogens on the basis of the results of in vitro and ex vivo experiments using cells of both human and animal origin. HSP70 and heat shock factor-1 (HSF1) are considered to be pharmacological targets of antiaging therapies ²⁶⁾. However, chemicals used to induce HSP70 are typically cytotoxic and therefore cannot be used by the target patient population (e.g., elderly individuals) who are more susceptible to stress. Fortunately, plant adaptogens have been used safely over a very wide dose range (up to 3000 mg/kg of rat body weight), even with repeated administration (over several months). The adaptogens Rhodiola, Schisandra, Eleutherococcus, and their combination as ADAPT-232 (with its active constituent salidroside) stimulate the expression of HSF-1 and heat shock protein 70 (HSP72) in isolated neuroglia, provoke HSP72 release from cells ²⁷⁾ and promote the increased expression of HSP70 in vivo ²⁸⁾. Chronic Rhodiola rosea use significantly ameliorated swimming-induced fatigue by promoting glycogen levels, increasing energy generated by lipogenic enzymes, and boosting defense mechanisms inclusive of HSP70 action ²⁹⁾. R. rosea root extract significantly upregulates HSP70 mRNA and protects skeletal muscle cells against chemically induced oxidation ³⁰⁾. Further, Schizandrin B pretreatment induces a time-dependent increase in HSP25 and HSP70 expression in rat heart and protects against myocardial ischemia–reperfusion injury ³¹⁾. The hepatic cytoprotective action of schizandrin B against acetaminophen-induced liver injury is also mediated, at least in part, by the induction of HSP27 and HSP70 in mice. Oral administration of schizandrin B increased HSP27 and HSP70 gene and protein expression in a time- and dose-dependent fashion ³²⁾.

Salidroside and extracts of Schisandra chinensis and R. rosea were found to be the most active inhibitors of stress-induced p-SAPK/p-JNK. It has been shown that oral supplements of rhodioloside, or extracts of Eleutherococcus senticosus, S. chinensis, or R. rosea, administered over a 7-day period to rabbits subject to restraint stress, significantly decreased their levels of stress-activated protein kinases (i.e., the phosphorylated forms of SAPK/JNK) in circulating blood ³³⁾.

Exercise can induce expression of HSP70, which acts as an antiaging agent. This upregulation contributes to the maintenance of muscle fiber integrity and facilitates muscle regeneration and recovery. On the other hand, HSP70 expression is reduced during muscle inactivity and aging. Dysfunction of HSP70 generation may drive muscle atrophy, contractile dysfunction, and reduce regenerative capacity (associated with aging). The beneficial effects of activating the biosynthesis of HSP70 in skeletal muscle have been established in animal studies, suggesting that HSP70 is a key therapeutic target for the treatment of various conditions that negatively affect skeletal muscle mass and function ³⁴⁾.

Figure 4. Hypothetical mechanism of action of adaptogens on the stress system in depression

Note: Stress-induced release of CRH from the hypothalamus, followed by release of ACTH from the pituitary, simulates release of adrenal hormones and NPY in order to cope with the stress. Feedback regulation of overreaction is initiated by cortisol release from the adrenal cortex, followed by binding to glucocorticoid receptors (GR) in the brain. This signal stops the further release of brain hormones, and the stress-induced increase in cortisol decreases to normal levels in the circulatory system. While short and mild stress (eustress) is essential to life, severe stress can cause disease depression, which is associated with generation of active oxygen-containing molecules, including nitric oxide, which is known to inhibit ATP formation. Stress-induced signaling protein JNK was found to inhibit GR; consequently, this feedback normalization is blocked and cortisol content in blood of depressive patients is permanently high. This is associated with impaired memory, impaired ability to concentrate, fatigue, and other symptoms. Adaptogens suppress elevated JNK and cortisol in stress and stimulate the formation of HSP70, which is known to inhibit JNK. Consequently, nitric oxide levels no longer increase and ATP generation is not suppressed.

What are the chemical structures of the principal active substances in adaptogenic plant extracts and their structure–function relationships ?

Currently, no systematic studies on the structure–function activities of purified adaptogens with their targets are available. However, the principal active ingredients of plant adaptogens (as investigated thus far) can be divided into two main chemical groups (Figure 5): (1) terpenoids, with a tetracyclic skeleton, such as cortisol and testosterone (ginsenosides, sitoindosides, cucurbitacines, and withanolides) and (2) aromatic compounds that are structurally similar to catecholamines or tyrosine, including lignans (eleutheroside E (E. senticosus) and schizandrin B (S. chinensis)), phenylpropane derivatives (syringin (E. senticosus), rosavin (R. rosea)), and phenylethane derivatives (salidroside (R. rosea)). A number of studies indicate direct interactions between ginsenosides and corticosteroid and estrogenic receptors.

Plants containing mainly tetracylic or pentacyclic terpenoids (ginseng, Withania, Rhaponticum, Bryonia, etc.) are presumed to act via the hypothalamic–pituitary–adrenal (HPA) axis, while plants (e.g., Rhodiola, Schisandra, etc.) containing predominantly phenolic compounds (phenylpropanoids, phenylethanoids, and their dimers [lignans]) are presumed to interact with elements of the efferent sympathoadrenal system (SAS).

Figure 5. Chemical structures of adaptogenic compounds of plant origin

What physiological functions and diseases can adaptogens influence ?

As our knowledge of cell and systems biology grows, new questions and challenges arise. One of these relates to specific indications for drug use in medicine. The one drug–one indication paradigm is ordinarily unsuitable for adaptogens, given their polyvalent mode of action and nonspecific effects on the immune, endocrine, and nervous systems.

Adaptogens normalize chronically increased cortisol/corticosterone in the blood and saliva of humans or animals ³⁵⁾ presumably owing to a direct interaction with glucocorticoid receptors. For example, it was shown that the ginsenoside Rg1 is a functional ligand of glucocorticoid receptors, and its direct interaction with glucocorticoid receptors ligand-binding sites has been demonstrated. Rg1 behaves as a partial agonist of glucocorticoid receptors (not an inhibitor). Interestingly, the ginsenoside Rb1 is a functional ligand of the ER, in particular, the β isoform ³⁶⁾ and may also have beneficial effects in the conditions described above.

All other mediators of the effects of adaptogens (e.g., nitric oxide, JNK, SAPK, HSP70, HSP25, and FOXO [DAF16]) play roles in chronic inflammation (common to all age-related diseases), such as that seen in muscle degeneration (sarcopenia), senile dementia, Alzheimer’s disease, atherosclerosis, cardiovascular disease, hypertension, osteoarthritis, type 2 diabetes, and obesity. Clearly, more randomized clinical trials of standardized botanicals are required if we are to implement these agents in medical practice for use in these specific indications.

Adaptogenic herbs

Current and potential uses of adaptogens in pharmacotherap are related to their treatment of mental diseases and behavioral disorders, stress-induced fatigue, and cognitive function ³⁷⁾, ³⁸⁾. However further studies are warranted if we are to understand the range of interactions between adaptogens and stress response pathways (both intracellular and extracellular) in terms of the metabolic regulation of homeostasis in stress- and age-associated disease.

Some adaptogenic plants (see Table 1) have been used in traditional Chinese medicine and Ayurveda for centuries to promote physical and mental health, improve the body’s defense mechanisms, and enhance longevity ³⁹⁾. However, further evidence, based on well-designed clinical trials with standardized herbal preparations, is required to support the efficacy of these traditional herbal medicines to qualify them as herbal medicinal products with well-established use in medicine. Moreover, the investigations of molecular mechanisms of action of adaptogens are required for understanding the polyvalent pharmacological activity of adaptogens. The reductionist concept of a single receptor-based view of drug action ⁴⁰⁾ would appear to be unsatisfactory for adaptogens. However, adaptogens exhibit multitarget action and the shared use of a number of different receptors, including receptors for corticosteroid, mineralocorticoid, progestin, estrogen, serotonin (5-HT), N-methyl-d-aspartate, and nicotinic acetylcholine, receptor tyrosine kinases, and many G protein–coupled receptors ⁴¹⁾. Therefore, the possibility that numerous molecular network interactions (with feedback regulation of the neuroendocrine and immune systems) contribute to the overall pharmacological response and result in agonist-dependent antagonism is most suitable for understanding the mechanisms of action of adaptogens. Thus, the pharmacology of adaptogens is a typical example of network pharmacology ⁴²⁾. Network pharmacology has the potential to provide treatments for complex diseases, chronic conditions, and syndromes, inclusive of their pathophysiologic evolution, where conventional approaches have often been disappointing ⁴³⁾. Adaptive stress responses include several stages and involve multiple molecular networks in which receptors interact with adaptogens ⁴⁴⁾.

Table 1. Plants cited in the literature with adaptogenic properties

Note: This table is an update from the reviews of Wagner et al. ⁴⁵⁾ and Panossian and Wagner ⁴⁶⁾. It includes plants that do and do not meet the formal definition of adaptogen.

The active components of stress-protective plants and adaptogens (see Table 2) can be formally divided into three main groups, namely, tetra(penta)cyclic terpenoids, phenyl- and phenylethyl-propanoids and derivatives, and oxylipins. On the basis of the chemical nature of their active principles, some indication of the possible mechanism of action of these plants may be derived. Thus, the extracts of Panax ginseng, Withania somnifera, Bryonia alba and Aralia mandshurica contain phytosterols, and tetracyclic and pentacyclic triterpenes, that likely exert their effect on the hypothalamus-pituitary-adrenal (HPA) axis in which cortisone plays a key role during stress. Typically these adaptogens prevent or at least decrease certain hormonal changes, such as the increased level of cortisone, that are characteristic of a stress reaction ⁴⁸⁾. Plants such as Rhodiola rosea and Schizandra chinensis accumulate phenolic secondary metabolites such as phenyl- and phenylethyl-propanoids and their dimeric lignans ⁴⁹⁾. Such compounds can play an active role in stress response in respect of achieving a state of maximum work capacity as would be required in fight-or-flight situations ⁵⁰⁾. Interestingly, Eleutherococcus senticosus contains both types of biologically active, low molecular weight compound and exhibits a very wide range of pharmacological effects ⁵¹⁾.

Table 2. Adaptogenic herbs

What is cumin

Cumin (Cuminum cyminum) is an annual, aromatic, herbaceous flowering plant in the family Apiaceae, native from the east Mediterranean to South Asia. Cumin seeds (each one contained within a fruit, which is dried) are used in the cuisines of many different cultures, in both whole and ground form. It also has many uses as a traditional medicinal plant.

Cumin is an important medicinal and spice crop cultivated in the arid and semi-arid regions of the world, where saline soil is widely distributed, unsuitable for agriculture ¹⁾. The cumin plant is good source of minerals like iron, copper, zinc and manganese and B-complex vitamins such as thiamine, niacin, riboflavin and antioxidant vitamins like A, E and C ²⁾. Cumin and value added products of cumin seeds have gained importance in functional food with wide range of health benefits, dietary supplements, cosmetics and other nutraceutical applications.

Previous studies have also reveal that cumin seeds are excellent source of secondary metabolites, such as polyphenols with free radical scavenging properties and have wide applications in food industries ³⁾. Major secondary metabolites isolated from cumin seed are 1-O-β-D-glucopyranoside ⁴⁾, β-D-glucopyranoside ⁵⁾ and cuminoside A and B ⁶⁾.

Figure 1. Cumin seeds (Cuminum cyminum)

Black cumin

Black cumin (Bunium bulbocastanum)  is related to cumin and has a smoky, earthy taste. But black cumin is often confused with Nigella sativa (which is also blackseed and black caraway). Dried black cumin fruits are used as a culinary spice in northern India, Pakistan, Bangladesh, Afghanistan, Tajikistan and Iran. It is practically unknown outside these areas. The tuber-like root is locally collected for food; the “pignut” or chestnut” names refer to it.

The small, rounded taproot is edible raw or cooked, and said to taste like sweet chestnuts. The leaf can be used as an herb or garnish similar to parsley.

The black cumin seeds are most valued as a garnish to high value, very special Indian dishes; they should not be ground as their flavor would be reduced.

Figure 2. Black cumin (Bunium bulbocastanum)

What is cumin used for

Cumin is globally popular and essential for flavoring in many cuisines, particularly South Asian, Northern African and Latin American cuisines ⁷⁾. Cumin seeds are used as a spice for their distinctive flavor and aroma. Cumin can be found in some cheeses, such as Leyden cheese, and in some traditional breads from France. Cumin can be an ingredient in chili powder (often Tex-Mex or Mexican-style), and is found in achiote blends, adobos, sofrito, garam masala, curry powder, and bahaarat. In South Asian cooking, it is often combined with coriander seeds in a powdered mixture called dhana jeera.

Cumin can be used ground or as whole seeds. It helps to add an earthy and warming feeling to food, making it a staple in certain stews and soups, as well as spiced gravies such as curry and chili. It is also used as an ingredient in some pickles and pastries.

Cumin Nutrition Facts

In a 100 gram amount, cumin seeds are nutritionally rich, providing high amounts of the Daily Value for fat (especially monounsaturated fat), protein and dietary fiber. Values for B vitamins, vitamin E, and several dietary minerals, especially iron, are also considerable when expressed in this 100 gram amount.

Cumin contains key nutrients such as iron and copper, which are needed for healthy red blood cells. Just one teaspoon of cumin seeds contains around 3mg of your daily iron intake (that’s 20% of daily iron intake for women and 34% for men).

Potassium, needed for controlling blood pressure and heart rate, can also be found in cumin along with zinc, which plays an important role in immune function.

Cumin also contains calcium, important for helping to build strong bones and teeth and regulating muscle contractions, as well as magnesium which aids the process of turning food into energy and is a natural relaxant.

Table 1. Cumin seeds

Cumin health benefits

The plant is an active reservoir of numerous bioactive compounds with various therapeutic applications ⁹⁾. A total of 45 differentially expressed metabolites were identified in cumin plants (see Table 2. below). Essential oil extracted by hydrodistillation from Tunisian cumin contain 21 active components and some of the major components are cuminlaldehyde (39.48%), gamma-terpinene (15.21%), O-cymene (11.82%), beta-pinene (11.13%), 2-caren-10-al (7.93%), trans-carveol (4.49%) and myrtenal (3.5%) ¹⁰⁾. Moreover, cumin oil exhibited higher antibacterial and antifungal activities with a high effectiveness against Vibrio spp. strains. On the other hand, the cumin oil was investigated for its antioxidant activities and the results showed that cumin oil exhibit a higher activity in each antioxidant system with a special attention for beta-carotene bleaching test and reducing power ¹¹⁾. In the light of these findings, some scientists suggested that cumin essential oil may be considered as an interesting source of antibacterial, antifungal and antioxidants components used as potent agents in food preservation and for therapeutic or nutraceutical industries.

Cumin is also used in the treatment of fever, loss of appetite, diarrhea, vomiting, abdominal distension, edema and puerperal disorders ¹²⁾, ¹³⁾. In traditional medicine of Tunisia, cumin is considered abortive, galactagogue (promotes or increases the flow of a mother’s milk), antiseptic, antihypertensive herb , while in Italy, it is used as bitter tonic, carminative (relieves flatulence) and purgative (laxative) ¹⁴⁾. In indigenous Arabic medicines, cumin seeds are documented as stimulant, carminative, and attributed with cooling affect and therefore form an ingredient of most prescriptions for gonorrhea, chronic diarrhea and dyspepsia; externally, they are applied in the form of poultice to allay pain and irritation of worms in the abdomen ¹⁵⁾. In Iranian traditional medicine, cumin is considered stimulant, carminative and astringent and its therapeutic effects have been described on gastrointestinal, gynecological and respiratory disorders, and also for the treatment of toothache, diarrhea and epilepsy ¹⁶⁾. Cumin seeds reduced to powder, mixed with honey, salt and butter are applied to scorpion bites ¹⁷⁾.

Cumin shoots own metabolites having various pharmacological activities, such as antimicrobial, anti-diabetic, antiepileptic anti-infertility, anticancer, antioxidant and immunomodulatory ¹⁸⁾, ¹⁹⁾. Cumin oil was found to attenuate seizures induced by maximal electroshock and pentylenetetrazol in mice ²⁰⁾. A methanolic extract of cumin seeds reduced the blood glucose and inhibited glycosylated hemoglobin, creatinine, blood urea nitrogen and improved serum insulin and glycogen (liver and skeletal muscle) content in alloxan and streptozotocin (STZ) diabetic rats ²¹⁾. Eight-week sub-acute administration of cumin to STZ-diabetic rats reduced hyperglycemia and glucosuria accompanied by an improvement in body weight, blood urea and reduced excretion of urea and creatinine ²²⁾. Oral administration of cumin also showed hypoglycemic effect in normal rabbit, resulting in significant decrease in the area under the glucose tolerance curve ²³⁾. Metabolites with bioactivity such as anticancerous (docetaxel) and antimicrobial (megalomicin) were also identified along with intermediate metabolites involved in different pathways. Gagandeep et al. ²⁴⁾ demonstrated that cumin has an anticancer effect and inhibits the induction of gastric squamous cell carcinomas in mice.

Numerous investigations have revealed a potential antimicrobial activity of cumin products (oils as well as their aqueous and solvent derived extracts). This antibacterial action was assessed against a range of useful and pathogenic gram-positive and gram-negative bacterial strains ²⁵⁾, ²⁶⁾. Cumin seed oil and alcoholic extract inhibited the growth of Klebsiella pneumoniae and its clinical isolates and caused improvement in cell morphology, capsule expression and decreased urease activity. This property was attributed to cuminaldehyde ²⁷⁾. Biofilm-formation preventive properties were found against Streptococcus mutans and Streptococcus pyogenes ²⁸⁾.

Cumin seeds are reported to be estrogenic ²⁹⁾. The presence of phytoestrogens in cumin has been shown and also related to its anti-osteoporotic effects. In the animals receiving a methanolic extract of cumin, a significant reduction in urinary calcium excretion and augmentation of calcium content and mechanical strength of bones was found. Animals showed greater bone and ash densities and improved microarchitecture, with no adverse effects like body weight gain and weight of atrophic uterus ³⁰⁾.

Oral administration of cumin to alloxan diabetic rats reduced body weight, plasma and tissue cholesterol, phospholipids, free fatty acids and triglycerides. Histological observations demonstrated significant decrease in fatty changes and inflammatory cell infiltrates in diabetic rat pancreas ³¹⁾. Cumin suppressed alcohol and thermally oxidized oil induced hyperlipidemia. It decreased aspartate transaminase (AST), alkaline phosphatase (ALP) and γ-glutamyl transferase (GGT) activities and decreased the tissue (liver and kidney) levels of cholesterol, triglycerides and phospholipids and prevented the changes in the composition of fatty acids in the plasma of rats administered with alcohol and/or thermally oxidized oil. The activity of phospholipase A and C decreased significantly ³²⁾. Hypocholesterolemic effect of methanolic extract of cumin is also documented in ovariectomized rat in relation to its anti-osteoporotic effect ³³⁾. Cumin added to a hypercholesterolemic diet decreased serum and liver cholesterol in rats ³⁴⁾.

In a recent study, oral treatment with cumin showed immunomodulatory properties in normal and immune-suppressed animals via modulation of T lymphocytes′ expression in a dose-dependent manner. It stimulated the T cells′ (CD4 and CD8) and Th1 cytokines′ expression in normal and cyclosporine-A induced immune-suppressed mice. In restraint stress-induced immune-suppressed animals, the active compound of cumin countered the depleted T lymphocytes, decreased the elevated corticosterone levels and size of adrenal glands and increased the weight of thymus and spleen ³⁵⁾.

Table 2. Probable metabolites and their possible application/ role identified in cumin 

Thus cumin seeds are of considerable importance because of its nutritional values and other health benefits. Dried cumin seeds contain volatile oil (5%), fat (22%), protein (10%), fibre (11%) and free amino acids ³⁷⁾. A diverse array of compounds have been revealed in essential oils, oleoresins and seeds of cumin; the major compounds occurring in cumin are cuminaldehyde, limonene, α- and β-pinene, 1,8-cineole, o- and p-cymene, α- and γ-terpinene, safranal and linalool. The characteristic aroma of volatile oil, obtained from dried cumin seeds are attributed to the presence of 3p-menthen-7al, β–pinene, p-cymene, γ-terpinene, p-mentha-1, 3-dien-7-al, p-mentha-1 and cuminaldehyde in combination with other related aldehydes ³⁸⁾. Cuminaldehyde, cymene and terpenoids are the major volatile components of cumin. Cuminaldehyde has also antimicrobial and antifungal properties, which could be shown with Escherichia coli and Penicillium chrysogenum ³⁹⁾. The anti-carcinogenic activity has also been studied and cumin seeds are found potent inhibitor of both squamous cell carcomas and hepatomas ⁴⁰⁾. In herbal medicine, cumin oil is known to possess several pharmacological activities, such as antimicrobial, anti-diabetic, antiepileptic, anti-infertility, anticancerous and immunomodulative effects due to presence of active chemical constituents. Aqueous or solvent extract of cumin is known to inhibit growth of many pathogenic micro-organisms ⁴¹⁾, ⁴²⁾.

What is coriander

Coriander (Coriandrum sativum Linn.), also known as cilantro  (in the US and in Canada) or Chinese parsley, is an annual herb in the family Apiaceae (Umbelliferae) that has been extensively cultivated for centuries in many temperate climates such as the Middle East, Latin American, Africa, and Asia ¹⁾. All parts of the coriander plant are edible, both the seeds and aerial parts of coriander are used as food elements, but the fresh leaves and the dried seeds are the parts most traditionally used in cooking.

All parts of the plant are edible, but the fresh leaves and the dried seeds are the parts most traditionally used in cooking. Coriander is used in cuisines throughout the world.

The leaves are variously referred to as coriander leaves, fresh coriander, dhania, Chinese parsley, or cilantro. Fresh leaves are used as a flavoring agent, and dried coriander seeds are used as spices in food preparation ²⁾.

Coriander leaves

The coriander leaves have a different taste from the seeds, with citrus overtones. In addition to volatile oils, caffeic acid and flavonoid glycosides have been isolated from coriander leaves ³⁾. Some people may be genetically predisposed to find the leaves to have unpleasant soapy taste or a rank smell. The fresh leaves are an ingredient in many South Asian foods (such as chutneys and salads); in Chinese and Thai dishes; in Mexican cooking, particularly in salsa and guacamole and as a garnish; and in salads in Russia. In Portugal, chopped coriander is used in the bread soup Açorda, and in India, chopped coriander is a garnish on Indian dishes such as dal. As heat diminishes their flavor, coriander leaves are often used raw or added to the dish immediately before serving. In Indian and Central Asian recipes, coriander leaves are used in large amounts and cooked until the flavor diminishes. The leaves spoil quickly when removed from the plant, and lose their aroma when dried or frozen.

Figure 1. Coriander leaf, seeds and root

Coriander seeds

The dry coriander fruits are known as coriander seeds. The word “coriander” in food preparation may refer solely to these seeds (as a spice), rather than to the plant. Coriander seeds have a lemony citrus flavor when crushed, due the seeds are essential oils and monoterpenoids, such as linalool and pinene. It is described as warm, nutty, spicy, and orange-flavored.

The variety Coriandrum sativum vulgare has a fruit diameter of 3–5 mm (0.12–0.20 in), while var. Coriandrum sativum microcarpum fruits have a diameter of 1.5–3 mm (0.06–0.12 in). Large-fruited types are grown mainly by tropical and subtropical countries, e.g. Morocco, India, and Australia, and contain a low volatile oil content (0.1-0.4%). They are used extensively for grinding and blending purposes in the spice trade. Types with smaller fruit are produced in temperate regions and usually have a volatile oil content around 0.4-1.8%, so are highly valued as a raw material for the preparation of essential oil.

Coriander is commonly found both as whole dried seeds and in ground form. Roasting or heating the seeds in a dry pan heightens the flavour, aroma, and pungency. Ground coriander seed loses flavour quickly in storage and is best ground fresh. Coriander seed is a spice in garam masala and Indian curries which often employ the ground fruits in generous amounts together with cumin, acting as a thickener in a mixture called dhana jeera.

Roasted coriander seeds, called dhana dal, are eaten as a snack. They are the main ingredient of the two south Indian dishes sambhar and rasam.

Outside of Asia, coriander seed is used widely in the process for pickling vegetables. In Germany and South Africa (see boerewors), the seeds are used while making sausages. In Russia and Central Europe, coriander seed is an occasional ingredient in rye bread (e.g. Borodinsky bread), as an alternative to caraway.

Coriander seeds are used in brewing certain styles of beer, particularly some Belgian wheat beers. The coriander seeds are used with orange peel to add a citrus character.

Coriander seed is one of the main traditional ingredients in the South African Boerewors, a popular spiced mixed-meat sausage.

Coriander Nutrition Facts

The nutritional profile of coriander seeds is different from the fresh stems or leaves. Leaves are particularly rich in vitamin A, vitamin C and vitamin K, with moderate content of dietary minerals. Although seeds generally have lower content of vitamins, they do provide significant amounts of dietary fiber, calcium, selenium, iron, magnesium and manganese.

Table 1. Coriander (cilantro) leaves, raw

Table 2. Coriander (cilantro) leaves, dried

Table 3. Coriander seeds

Coriander health benefits

Coriander leaves and seeds are widely used in folk medicine as a cholesterol-lowering agent, a digestive stimulant, and an anti-hypertensive agent ⁷⁾, in addition to its use as a seasoning in food preparation. Pharmaceutical applications of coriander have also revealed antibacterial ⁸⁾, antioxidant ⁹⁾, hepatoprotective ¹⁰⁾ and anticonvulsant ¹¹⁾ activities.

The essential oil from coriander has been proven in test tube and petri dish studies to have a strong antifungal effect against Candida species ¹²⁾. However, most studies have analyzed the essential oil from fruits ¹³⁾ and seeds ¹⁴⁾, which have a different chemical composition from those present in the leaves ¹⁵⁾. Previous studies have shown that the major components of coriander leaf essential oil are alcohols and aldehydes ¹⁶⁾ with decanal, trans-2-decenal, 2-decen-1-ol and cyclodecane as the most prominent compounds ¹⁷⁾. Most of these analytes have also been found as major constituents of coriander leaf samples from Kenya, U.S., Bangladesh, Fiji and Brazil. The mono- and sesquiterpenes found in coriander leaf essential oil may be related to the antifungal activity observed. Natural products are considered strong inhibitors of microbial activity when minimum inhibitory concentration [MIC] (the lowest concentration of a chemical which prevents visible growth of a microorganism) values are lower than 500 µg/ml ¹⁸⁾.

In the contrary, Sagdic et al. ¹⁹⁾ tested 18 extracts of plant spices commonly grow in Turkey including coriander (Coriandrum sativum) against 23 microorganisms. Coriander did not show bactericidal activity ²⁰⁾. Ates et al. ²¹⁾ studied 5 plants extracts against 13 bacteria. Coriander had no antibacterial effect to the microorganisms tested. Chaudhury et al. ²²⁾ used aqueous decoction of 4 plants against oral pathogens. Similar to our results, coriander did not exhibit any antibacterial activity to the tested organisms ²³⁾.

Pharmacological studies in animals have shown that coriander has anti-diabetic ²⁴⁾, hypolipidemic, ²⁵⁾ and anti-cancer effects ²⁶⁾. Sedative-hypnotic activity of coriander seeds have been evaluated in scientific studies in mice ²⁷⁾. Linalool, the main monoterpenoids of coriander seeds is shown to have sedative and anticonvulsant activity in animal studies and anxiolytic and sedative activity in human studies ²⁸⁾. Report also states the in vivo antioxidant activities of coriander seed ²⁹⁾.

In another test tube study, the ethyl acetate extract of coriander root has antioxidant and anticancer properties. Coriander root inhibited DNA damage in fibroblasts and prevented MCF-7 breast cancer cell migration induced by H₂O₂, suggesting its potential in cancer prevention and inhibition of metastasis ³⁰⁾. The herb exhibited anticancer activity in MCF-7 breast cancer cells by affecting antioxidant enzymes leading to H₂O₂ accumulation, cell cycle arrest at the G₂/M phase and apoptotic cell death by the death receptor and mitochondrial apoptotic pathways. High levels of H₂O₂ can produce cancer cell death ³¹⁾.

Summary

Although coriander has been reported to possess a wide range of traditional medicinal uses, there are currently no well designed clinical trials to corroborate those traditional medicine uses of coriander. Therefore we do not recommend using coriander as therapeutic medicine, instead we support coriander uses in foods and cooking.

What is acupuncture

Acupuncture is a technique of insertion and manipulation of fine needles in specific points on the body to achieve therapeutic purposes ¹⁾. The acupuncture technique that has been most often studied scientifically involves penetrating the skin with thin, solid, metallic needles that are manipulated by the hands or by electrical stimulation.

Acupuncture has been practiced widely in China for more than 4000 years and is an integral part of traditional Chinese medicine. It was first described in the medical writings The Yellow Emperor’s Classic of Internal Medicine1 around 200 BC. As early as 5000 years ago, stones were sculpted and formed into crude needles to be used as medical instruments ²⁾. In time, other materials, including bamboo, fish bones, bronze, gold, and silver, have been refined into acupuncture needles.

Modern acupuncture needles are thin and flexible and are made of solid surgical stainless steel. Unlike hypodermic needles, acupuncture needles are finely tapered, allowing them to slide smoothly into the skin (see Figure 1). Certain acupuncture needles are thinner than the average strand of human hair.

Figure 1. Comparison of acupuncture needles with a 20-gauge hypodermic needle. Matchstick shown for indication of needle sizes

Acupuncture is based on the idea that living beings have an inner energy, known as Qi (pronounced chee), and it is the flow of this inner energy that sustains them. According to traditional Chinese medical philosophy, balanced Qi is vital to optimal health; illness and disease are caused by the imbalance or interruption in the flow of Qi. Although acupuncture was developed for prevention of illness, it is useful in managing disease symptoms by reintroducing balanced flow of Qi, its main focus. According to the philosophy of traditional acupuncture, energy circulates in ‘meridians’ located throughout the body. Pain or ill health happens when something occurs to cause this meridian energy circulation to be blocked. The way to restore health is to stimulate the appropriate combination of acupuncture points in the body by inserting very thin needles. Sometimes in painful conditions, electrical stimulation along with the needles is also used. According to acupuncture theory, one way you can tell that acupuncture is relieving pain is that you may feel numbness or tingling, called De Qi, where the needle is inserted.

Jesuit missionaries introduced acupuncture to Europe in the 17th century, when they returned from China. The Jesuits were active in disseminating the idea and practice of acupuncture throughout Europe. In addition, traveling physicians helped pioneer acupuncture use in Europe ³⁾.

In the United States, acupuncture gained public and professional attention in 1971, when New York Times reporter James Reston wrote about his experience with acupuncture after an emergency appendectomy in China ⁴⁾. The operation was a success, but Reston soon had a considerable amount of postoperative pain and bloating. To provide relief, Chinese physicians offered acupuncture as a therapeutic modality. Reston, impressed by the effectiveness of this “ancient” procedure, described the overall improvement of his symptoms with no recurrence afterward. Through his newspaper article, he exposed countless Americans to acupuncture for the first time.

Today millions of Americans use acupuncture each year, often for chronic pain, but there has been considerable controversy surrounding its value as a therapy and whether it is anything more than placebo. Research exploring a number of possible mechanisms for acupuncture’s pain-relieving effects is ongoing.

Research suggests that acupuncture can help manage certain pain conditions – may help ease types of pain that are often chronic such as low-back pain, neck pain, and osteoarthritis/knee pain, but evidence about its value for other health issues is uncertain.

Acupuncture also may help reduce the frequency of tension headaches and prevent migraine headaches. Therefore, acupuncture appears to be a reasonable option for people with chronic pain to consider. However, clinical practice guidelines are inconsistent in recommendations about acupuncture.

The effects of acupuncture on the brain and body and how best to measure them are only beginning to be understood. Current evidence suggests that many factors—like expectation and belief—that are unrelated to acupuncture needling may play important roles in the beneficial effects of acupuncture on pain.

How does acupuncture work

There are many theories that may explain how acupuncture works. Many studies in animals and humans have demonstrated that acupuncture can cause multiple biological responses, including circulatory and biochemical effects. These responses can occur locally or close to the site of application or at a distance. They are mediated mainly by sensory neurons to many structures within the central nervous system. This can lead to activation of pathways affecting various physiological systems in the brain as well as in the periphery ⁵⁾. In summary, possible mechanisms of the effects of acupuncture on neurological conditions include stimulation of neuronal cell proliferation ⁶⁾, facilitation of neural plasticity ⁷⁾, reduction of the post-ischaemic inflammatory reaction ⁸⁾ and prevention of neuronal apoptosis ⁹⁾.

Figure 2. Acupuncture points

Gate Control Theory of Pain

This theory postulates that specific nerve fibers transmit a pain signal to the brain via the spinal cord, and input of other nerve fibers can inhibit the pain signal transmission ¹⁰⁾. Acupuncture is thought to stimulate inhibitory nerve fibers for a short period, thus reducing transmission of the pain signal to the brain.

Endorphin Model

During the 1970s, researchers isolated endogenous endorphins in the central nervous system. Clinical studies reported that inserting acupuncture needles into specific acupuncture points triggered the production of endorphins in cerebrospinal fluid after patients underwent acupuncture treatments ¹¹⁾. The pain-alleviating effects of acupuncture were reduced when naloxone was used to pretreat the patient, which may indicate that acupuncture-induced analgesia may be partly mediated through endogenous opioids ¹²⁾.

Recent research has found that traditional Chinese medicine acupuncture therapy has a direct effect in the up-regulation of μ-opioid receptor binding availability in the central nervous system compared with placebo (sham) acupuncture ¹³⁾. This finding may help explain some of the analgesic effects seen with acupuncture therapy.

Neurotransmitter Model

Research in animals has found that acupuncture can modulate serotonin, norepinephrine, and neurons that transmit or secrete γ-aminobutyric acid ¹⁴⁾. It is postulated that through the neurotransmitter model, acupuncture can be efficacious for treatment of depression, anxiety, and addiction.

Other Theories

Other theories postulate that acupuncture indirectly influences the autonomic system. Acupuncture treatment can affect respiration, heart rate, blood pressure, circulation, and immune function ¹⁵⁾. Research indicates the increased electrical conductivity of tissues along acupuncture meridians ¹⁶⁾. This result suggests that manipulation of the acupuncture meridians with needles may modulate the transmission of certain signals within the body. The current scientific theories provide a basis for stating that acupuncture has an effect on the nervous system, but its effects cannot be explained with a single mechanism.

Who Provides Acupuncture Treatments ?

Nonphysician, licensed acupuncturists provide most acupuncture treatments in the United States. Although formal training programs differ from state to state, the National Certification Commission for Acupuncture and Oriental Medicine has developed rigorous certification criteria and examination requirements for licensed acupuncturists. The licensing mandates of a state should be checked to ensure the qualifications of a practitioner before a patient begins acupuncture treatment by that practitioner.

If you decide to visit an acupuncturist, check his or her credentials. Most states require a license, certification, or registration to practice acupuncture; however, education and training standards and requirements for obtaining these vary from state to state. Although a license does not ensure quality of care, it does indicate that the practitioner meets certain standards regarding the knowledge and use of acupuncture. Most states require a diploma from the National Certification Commission for Acupuncture and Oriental Medicine for licensing.

With the growth of integrative medicine, more physicians are seeking formal training in medical acupuncture. Physicians trained in medical acupuncture may be desirable practitioners, especially in complex cases in which conventional allopathic therapies need to be considered in developing an integrative treatment plan. The American Academy of Medical Acupuncture is a physician resource for training and certification.

Ask the practitioner about the estimated number of treatments needed and how much each treatment will cost. Some insurance companies may cover the costs of acupuncture, while others may not.

• Don’t use acupuncture to postpone seeing a health care provider about a health problem. Help your health care providers give you better coordinated and safe care by telling them about all the health approaches you use. Give them a full picture of what you do to manage your health.

Acupuncture therapy

The Chinese people continue to use acupuncture as a primary healing modality for the prevention and treatment of most ailments. In the United States, physicians and patients most frequently request acupuncture as an adjuvant therapy for managing conditions associated with acute and chronic pain. These conditions range across different neurologic, musculoskeletal, and gastrointestinal symptoms (see Table 1). As acceptance of acupuncture increases within the medical community, the scope of acupuncture practice will likely broaden to mirror what is practiced worldwide to include non–pain-related conditions. These changing trends are likely to lead to additional research efforts focused on conditions in which a paucity of evidence for use exists.

Table 1. Traditional Uses of Acupuncture Therapy

Note: COPD = chronic obstructive pulmonary disease; ENT = ear, nose, throat; IBS = irritable bowel syndrome; PMS = premenstrual syndrome.

Acupuncture benefits

What Does the Evidence Show ?

Although acupuncture has been used for thousands of years in Asia, the research community has started studying it only in the past few decades. The nature of acupuncture therapy involves tailoring treatments to the individual patient, and thus research on acupuncture has been difficult because of variable treatment interventions, techniques, and study size. Meta-analysis studies of acupuncture are limited because of the heterogeneity of pooling acupuncture treatment data.

Stroke Rehabilitation

A 2016 Cochrane review ¹⁸⁾ involving 31 trials with a total of 2257 participants in the subacute or chronic stages of stroke. Two trials compared real acupuncture plus baseline treatment with sham acupuncture plus baseline treatment. There was no evidence of differences in the changes of motor function and quality of life between real acupuncture and sham acupuncture for people with stroke in the convalescent stage. Twenty-nine trials compared acupuncture plus baseline treatment versus baseline treatment alone. Compared with no acupuncture, for people with stroke in the convalescent phase, acupuncture had beneficial effects on the improvement of dependency (activity of daily living). The review authors conclusion was that acupuncture may have beneficial effects on improving dependency, global neurological deficiency, and some specific neurological impairments for people with stroke in the convalescent stage, with no obvious serious adverse events ¹⁹⁾. However, most included trials were of inadequate quality and size. There is, therefore, inadequate evidence to draw any conclusions about its routine use ²⁰⁾. Rigorously designed, randomized, multi-center, large sample trials of acupuncture for stroke are needed to further assess its effects.

Period Pain

Another good quality review conducted in 2016 ²¹⁾ included 42 randomized controlled trials (4640 women). Acupuncture or acupressure was compared with a sham/placebo group, medication, no treatment or other treatment. Many of the continuous data were not suitable for calculation of means, mainly due to evidence of skew. The finding of that good quality review was there is insufficient evidence to demonstrate whether or not acupuncture or acupressure are effective in treating primary dysmenorrhoea (period pain) and for most comparisons no data were available on adverse events ²²⁾. The quality of the evidence was low or very low for all comparisons. The main limitations were risk of bias, poor reporting, inconsistency and risk of publication bias.

Peripheral Joint Osteoarthritis

In 2010 a Cochrane Review ²³⁾ was conducted to assess the effects of acupuncture for treating peripheral joint osteoarthritis. Sixteen trials involving 3498 people were included. Twelve of the randomized controlled trials included only people with osteoarthritis of the knee, 3 only osteoarthritis of the hip, and 1 a mix of people with osteoarthritis of the hip and/or knee. In comparison with a sham control, acupuncture showed statistically significant, short-term improvements in osteoarthritis pain; however, these benefits are small, do not meet the review authors pre-defined thresholds for clinical relevance and are probably due at least partially to placebo effects from incomplete blinding ²⁴⁾. Waiting list-controlled trials of acupuncture for peripheral joint osteoarthritis suggest statistically significant and clinically relevant benefits, much of which may be due to expectation or placebo effects ²⁵⁾.

Best estimate of what happens to people with osteoarthritis who have acupuncture ²⁶⁾:

Pain after 8 weeks:

• People who had acupuncture rated their pain to be improved by about 4 points on a scale of 0 to 20.
• People who received sham acupuncture rated their pain to be improved by about 3 points on a scale of 0 to 20.
• People who received acupuncture had a 1 point greater improvement on a scale of 0-20. (5% absolute improvement).

Pain after 26 weeks:

• People who had acupuncture rated their pain to be improved by slightly more than 3 points on a scale of 0 to 20.
• People who received sham acupuncture rated their pain to be improved by slightly less than 3 points on a scale of 0 to 20.
• People who received acupuncture had under a 1 point greater improvement on a scale of 0-20. (2% absolute improvement).

Physical function after 8 weeks :

• People who had acupuncture rated their function to be improved by about 11 points on a scale of 0 to 68.
• People who received sham acupuncture rated their function to be improved by about 8 points on a scale of 0 to 68.
• People who received acupuncture had about a 3 point greater improvement on a scale of 0-68. (4% absolute improvement)

Physical function after 26 weeks :

• People who had acupuncture rated their function to be improved by about 11 points on a scale of 0 to 68.
• People who received sham acupuncture rated their function to be improved by about 10 points on a scale of 0 to 68.
• People who received acupuncture had about a 1 point greater improvement on a scale of 0-68. (2% absolute improvement).

Rheumatoid arthritis

A good quality systematic review ²⁷⁾ was conducted to evaluate the effects of acupuncture or electro-acupuncture on the objective and subjective measures of disease activity in patients with rheumatoid arthritis. Although the results of the study on electro-acupuncture show that electro-acupuncture may be beneficial to reduce symptomatic knee pain in patients with rheumatoid arthritis 24 hours and 4 months post treatment, the reviewers concluded that the poor quality of the trial, including the small sample size preclude its recommendation. The reviewers further conclude that acupuncture has no effect on ESR, CRP, pain, patient’s global assessment, number of swollen joints, number of tender joints, general health, disease activity and reduction of analgesics ²⁸⁾. These conclusions are limited by methodological considerations such as the type of acupuncture (acupuncture vs electroacupuncture), the site of intervention, the low number of clinical trials and the small sample size of the included studies.

Fibromyalgia

One in five fibromyalgia sufferers use acupuncture treatment within two years of diagnosis. In 2013 a Cochrane Review ²⁹⁾ was conducted to examine the benefits and safety of acupuncture treatment for fibromyalgia. Nine trials (395 participants) were included. All studies except one were at low risk of selection bias; five were at risk of selective reporting bias (favoring either treatment group); two were subject to attrition bias (favoring acupuncture); three were subject to performance bias (favoring acupuncture) and one to detection bias (favoring acupuncture). Three studies utilized electro-acupuncture with the remainder using manual acupuncture without electrical stimulation. All studies used ‘formula acupuncture’ except for one, which used trigger points.

There was low to moderate-level evidence that compared with no treatment and standard therapy, acupuncture improves pain and stiffness in people with fibromyalgia ³⁰⁾. There is moderate-level evidence that the effect of acupuncture does not differ from sham acupuncture in reducing pain or fatigue, or improving sleep or global well-being. Electro-acupuncture is probably better than manual acupuncture for pain and stiffness reduction and improvement of global well-being, sleep and fatigue. The effect lasts up to one month, but is not maintained at six months follow-up. Manual acupuncture probably does not improve pain or physical functioning. Acupuncture appears safe. People with fibromyalgia may consider using electro-acupuncture alone or with exercise and medication. The small sample size, scarcity of studies for each comparison, lack of an ideal sham acupuncture weaken the level of evidence and its clinical implications. Larger studies are warranted.

Neuropathic pain in adults

Neuropathic pain may be caused by nerve damage, and is often followed by changes to the central nervous system. Due to the limited data available, there is insufficient evidence to support or refute the use of acupuncture for neuropathic pain in general, or for any specific neuropathic pain condition when compared with sham acupuncture or other active therapies ³¹⁾. Five studies are still ongoing and seven studies are awaiting classification due to the unclear treatment duration, and the results of these studies may influence the current findings.

Cancer pain in adults

Forty per cent of individuals with early or intermediate stage cancer and 90% with advanced cancer have moderate to severe pain and up to 70% of patients with cancer pain do not receive adequate pain relief. Five randomized controlled trials with 285 participants were included in this review ³²⁾. All studies had a high risk of bias from inadequate sample size and a low risk of bias associated with random sequence generation. Only three studies had low risk of bias associated with incomplete outcome data, while two studies had low risk of bias associated with allocation concealment and one study had low risk of bias associated with inadequate blinding. In conclusion, there is insufficient evidence to judge whether acupuncture is effective in treating cancer pain in adults.

Shoulder pain

In 2005 a well conducted review ³³⁾ was done to determine the efficacy and safety of acupuncture in the treatment of adults with shoulder pain. Nine trials of varying methodological quality met the inclusion criteria. For all trials there was poor description of interventions. Varying placebos were used in the different trials. There was no significant difference in short-term improvement associated with acupuncture when compared to placebo. In conclusion, due to a small number of clinical and methodologically diverse trials, little can be concluded from this review. There is little evidence to support or refute the use of acupuncture for shoulder pain although there may be short-term benefit with respect to pain and function. There is a need for further well designed clinical trials.

Lateral elbow pain

There is insufficient evidence to either support or refute the use of acupuncture (either needle or laser) in the treatment of lateral elbow pain. This review ³⁴⁾ has demonstrated needle acupuncture to be of short term benefit with respect to pain, but this finding is based on the results of 2 small trials, the results of which were not able to be combined in meta-analysis. No benefit lasting more than 24 hours following treatment has been demonstrated. No trial assessed or commented on potential adverse effect. Further trials, utilizing appropriate methods and adequate sample sizes, are needed before conclusions can be drawn regarding the effect of acupuncture on tennis elbow.

Low-Back Pain

• A 2012 analysis of data on participants in acupuncture studies looked at back and neck pain together and found that actual acupuncture was more helpful than either no acupuncture or simulated acupuncture.
• A 2010 review by the Agency for Healthcare Research and Quality found that acupuncture relieved low-back pain immediately after treatment but not over longer periods of time.
• A 2008 systematic review of studies on acupuncture for low-back pain found strong evidence that combining acupuncture with usual care helps more than usual care alone. The same review also found strong evidence that there is no difference between the effects of actual and simulated acupuncture in people with low-back pain.
  Clinical practice guidelines issued by the American Pain Society and the American College of Physicians in 2007 recommend acupuncture as one of several nondrug approaches physicians should consider when patients with chronic low-back pain do not respond to self-care (practices that people can do by themselves, such as remaining active, applying heat, and taking pain-relieving medications).
• Clinical practice guidelines issued by the American Pain Society and the American College of Physicians in 2007 recommend acupuncture as one of several nondrug approaches physicians should consider when patients with chronic low-back pain do not respond to self-care (practices that people can do by themselves, such as remaining active, applying heat, and taking pain-relieving medications).

Neck Pain

• A 2009 analysis found that actual acupuncture was more helpful for neck pain than simulated acupuncture, but the analysis was based on a small amount of evidence (only three studies with small study populations).
• A large German study with more than 14,000 participants evaluated adding acupuncture to usual care for neck pain. The researchers found that participants reported greater pain relief than those who didn’t receive it; the researchers didn’t test actual acupuncture against simulated acupuncture.

Headache

• A 2012 analysis of data on individual participants in acupuncture studies looked at migraine and tension headaches. The analysis showed that actual acupuncture was more effective than either no acupuncture or simulated acupuncture in reducing headache frequency or severity.
• A 2009 systematic review of studies concluded that actual acupuncture, compared with simulated acupuncture or pain-relieving drugs, helped people with tension-type headaches. A 2008 systematic review of studies suggested that actual acupuncture has a very slight advantage over simulated acupuncture in reducing tension-type headache intensity and the number of headache days per month.
• A 2009 systematic review found that adding acupuncture to basic care for migraines helped to reduce migraine frequency. However, in studies that compared actual acupuncture with simulated acupuncture, researchers found that the differences between the two treatments may have been due to chance.

Episodic migraine

In a Cochrane Review ³⁵⁾, twenty-two trials involving 4985 participants, acupuncture was associated with a moderate reduction of headache frequency over no acupuncture after treatment. The available evidence suggests that adding acupuncture to symptomatic treatment of attacks reduces the frequency of headaches. The updated evidence ³⁶⁾ also suggests that there is an effect over sham, but this effect is small. The available trials also suggest that acupuncture may be at least similarly effective as treatment with prophylactic drugs. Acupuncture can be considered a treatment option for patients willing to undergo this treatment. As for other migraine treatments, long-term studies, more than one year in duration, are lacking.

Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents

Attention Deficit Hyperactivity Disorder (ADHD) is a common childhood psychiatric disorder with features of inattention, hyperactivity and impulsivity.

A comprehensive search showed that there is no evidence base of randomized or quasi-randomized controlled trials to support the use of acupuncture as a treatment for ADHD in children and adolescents. Due to the lack of trials, we cannot reach any conclusions about the efficacy and safety of acupuncture for ADHD in children and adolescents. This excellent quality review ³⁷⁾ highlights the need for further research in this area in the form of high quality, large scale, randomized controlled trials.

Autism spectrum disorders (ASD)

Autism spectrum disorders (ASD) are lifelong disorders of development. People with ASD have particular difficulties with social interaction and communication and they lack flexibility in their thinking and behavior. No cure is currently available but interventions may improve symptoms.

Current evidence does not support the use of acupuncture for treatment of ASD ³⁸⁾ high quality trials of larger size and longer follow-up are needed.

Induction of labour

Induction of labour is offered to pregnant women when it is thought the outcome will be better for the mother or her baby if the pregnancy does not continue and the baby is born. Common reasons for induction include the pregnancy going beyond the due date, pre-term or pre-labour rupture of the membranes, and concerns about the health of the mother or baby such as pre-eclampsia or poor growth of the baby.

Overall, there was no clear benefit from acupuncture or acupressure in reducing caesarean section rate ³⁹⁾. The quality of the evidence varied between low to high. Few trials reported on neonatal morbidity or maternal mortality outcomes. Acupuncture showed some benefit in improving cervical maturity, however, more well-designed trials are needed. Future trials could include clinically relevant safety outcomes.

Pain management in labour

Many women would like to avoid pharmacological or invasive methods of pain management in labour and this may contribute towards the popularity of complementary methods of pain management. A systematic review was done in 2011 using 13 trials with data reporting on 1986 women ⁴⁰⁾. Nine trials reported on acupuncture and four trials reported on acupressure. Less intense pain was found from acupuncture compared with no intervention. Pain intensity was reduced in the acupressure group compared with a placebo control. In conclusion, acupuncture and acupressure may have a role with reducing pain, increasing satisfaction with pain management and reduced use of pharmacological management ⁴¹⁾. However, there is a need for further research.

Glaucoma

In 2013 Cochrane Review ⁴²⁾ to assess the effectiveness and safety of acupuncture in people with glaucoma. The review found that it is impossible to draw reliable conclusions from available data to support the use of acupuncture for the treatment of glaucoma. Because of ethical considerations, randomized controlled trials comparing acupuncture alone with standard glaucoma treatment or placebo are unlikely to be justified in countries where the standard of care has already been established ⁴³⁾. Because most glaucoma patients currently cared for by ophthalmologists do not use nontraditional therapy, clinical practice decisions will have to be based on physician judgments and patient preferences, given this lack of data in the literature. Inclusion of the seven Chinese trials in future updates of this review may change their conclusions.

Slowing the progression of myopia in children and adolescents

Myopia (near-sightedness or short-sightedness) is one of the three commonly detected refractive (focusing) errors. Two trials are included in this review ⁴⁴⁾ but no conclusions can be drawn for the benefit of co-acupressure for slowing progress of myopia in children. Further evidence in the form of randomized controlled trials are needed before any recommendations can be made for the use of acupuncture treatment in clinical use. These trials should compare acupuncture to placebo and have large sample sizes. Other types of acupuncture (such as auricular acupuncture) should be explored further as well as compliance with treatment for at least six months or longer. Axial length elongation of the eye should be investigated for at least one year. The potential to reduce/eliminate pain from acupuncture experienced by children should also be reviewed.

Depression

A good quality review ⁴⁵⁾ examined the effectiveness and adverse effects of acupuncture in the treatment for depression. The review found there was a high risk of bias in the majority of trials. There was insufficient evidence of a consistent beneficial effect from acupuncture compared with a wait list control or sham acupuncture control. The reviewers found insufficient evidence to recommend the use of acupuncture for people with depression ⁴⁶⁾. The results are limited by the high risk of bias in the majority of trials meeting inclusion criteria.

Epilepsy

A Cochrane Review was conducted in 2014 ⁴⁷⁾ to determine the effectiveness and safety of acupuncture in people with epilepsy. There were 17 randomized controlled trials with 1538 participants that had a wide age range and were suffering mainly from generalized epilepsy. The duration of treatment varied from 7.5 weeks to 1 year. All included trials had a high risk of bias with short follow-up. Compared with Chinese herbs, needle acupuncture plus Chinese herbs was not effective in achieving at least 50% reduction in seizure frequency (80% in control group versus 90% in intervention group. Based on those small, heterogeneous and high risk of biased evidence, the use of acupuncture for treating epilepsy cannot be supported.

Acute hordeolum (Stye infection)

Hordeolum is an acute, purulent inflammation of the eyelid margin usually caused by obstructed orifices of the sebaceous glands of the eyelid. The condition, which affects sebaceous glands internally or externally, is common. A Cochrane Review ⁴⁸⁾ was conducted to investigate the effectiveness and safety of acupuncture to treat acute hordeolum compared with no treatment, sham acupuncture, or other active treatment. There was low-certainty evidence suggesting that acupuncture with or without conventional treatments may provide short-term benefits for treating acute hordeolum when compared with conventional treatments alone. The certainty of the evidence was low to very low mainly due to small sample sizes, inadequate allocation concealment, lack of masking of the outcome assessors, inadequate or unclear randomization method, and a high or unreported number of dropouts. All randomized controlled trials were conducted in China, which may limit their generalizability to non-Chinese populations.

Because no randomized controlled trials included a valid sham acupuncture control, we cannot rule out a potential expectation/placebo effect associated with acupuncture. As resolution is based on clinical observation, the outcome could be influenced by the observer’s knowledge of the assigned treatment. Adverse effects of acupuncture were reported sparsely in the included randomized controlled trials and, when reported, were rare. Randomized controlled trials with better methodology, longer follow-up, and which are conducted among other populations are warranted to provide more general evidence regarding the benefit of acupuncture to treat acute hordeolum.

Bell’s palsy

Bell’s palsy or idiopathic facial palsy is an acute facial paralysis due to inflammation of the facial nerve. A number of studies published in China have suggested acupuncture is beneficial for facial palsy. A quality review ⁴⁹⁾ was conducted to examine the efficacy of acupuncture in hastening recovery and reducing long-term morbidity from Bell’s palsy. The quality of the included trials was inadequate to allow any conclusion about the efficacy of acupuncture. More research with high quality trials is needed.

Insomnia

A 2012 Cochrane Review ⁵⁰⁾ involving thirty-three trials were included to determine the efficacy and safety of acupuncture for insomnia. They recruited 2293 participants with insomnia, aged 15 to 98 years, some with medical conditions contributing to insomnia (stroke, end-stage renal disease, perimenopause, pregnancy, psychiatric diseases). They evaluated needle acupuncture, electro-acupuncture, acupressure or magnetic acupressure. Due to poor methodological quality, high levels of heterogeneity and publication bias, the current evidence is not sufficiently rigorous to support or refute acupuncture for treating insomnia. Larger high-quality clinical trials are required.

Restless legs syndrome

Restless legs syndrome is a sensorimotor movement disorder characterized by uncomfortable sensations in the legs and an urge to move them. The syndrome is very common and its lifestyle impacts justify a search for more effective and acceptable interventions. There is insufficient evidence to support the use of acupuncture for the symptomatic treatment of restless legs syndrome ⁵¹⁾.

Cocaine dependence

More than 400 substance abuse clinics in the USA and Europe offer a treatment for cocaine dependence called auricular acupuncture. In this treatment, needles are usually inserted into five specific points in the ear, but some clinics use only four or three of the points. In this Cochrane review ⁵²⁾ the authors set out to discover whether auricular acupuncture is effective in treating cocaine dependence and whether the number of points used makes a difference. There is currently no evidence that auricular acupuncture is effective for the treatment of cocaine dependence ⁵³⁾. The evidence is not of high quality and is inconclusive. Further randomized trials of auricular acupuncture may be justified.

Smoking cessation

Although pooled estimates suggest possible short-term effects there is no consistent, bias-free evidence that acupuncture, acupressure, or laser therapy have a sustained benefit on smoking cessation for six months or more ⁵⁴⁾. However, lack of evidence and methodological problems mean that no firm conclusions can be drawn. Electrostimulation is not effective for smoking cessation. Well-designed research into acupuncture, acupressure and laser stimulation is justified since these are popular interventions and safe when correctly applied, though these interventions alone are likely to be less effective than evidence-based interventions.

Uterine fibroids

Uterine fibroids are benign growths within the uterine muscle and are present in 30% of women during their reproductive years. To assess the benefits and harms of acupuncture in women with uterine fibroids, as systematic review ⁵⁵⁾ was done. No randomized double-blind controlled trials met the inclusion criteria. The effectiveness of acupuncture for the management of uterine fibroids remains uncertain. More evidence is required to establish the efficacy and safety of acupuncture for uterine fibroids. There is a continued need for well designed randomized controlled trials with long term follow up.

Endometriosis

Endometriosis is a gynaecological disease that causes chronic pelvic pain, most notably painful menstruation, as the most common complaint.

The evidence to support the effectiveness of acupuncture for pain in endometriosis is limited, based on the results of only a single study that was included in this review ⁵⁶⁾. This review examined the effectiveness of acupuncture for reducing pain in endometriosis; however only one study met our inclusion criteria. The data from the included study, involving 67 women, indicated that ear acupuncture is more effective compared to Chinese herbal medicine for reducing menstrual pain. The study did not report whether participants suffered any side effects from their treatments. Larger, well-designed studies comparing acupuncture with conventional therapies are necessary to confirm these results.

Polycystic ovarian syndrome

Polycystic ovarian syndrome (PCOS) is where women have small cysts on their ovaries (organs that produce eggs) and is characterised by the clinical signs of infrequent or very light menstruation (periods), failure to conceive (become pregnant) and excessive hair growth. Thus far, only a limited number of randomized controlled trials have been reported. At present, there is insufficient evidence to support the use of acupuncture for treatment of ovulation disorders in women with PCOS ⁵⁷⁾.

Menopausal hot flushes

Hot flushes are the most common menopausal vasomotor symptom. Hormone therapy has frequently been recommended for relief of hot flushes, but concerns about the health risks of hormone therapy have encouraged women to seek alternative treatments.A Cochrane Review found insufficient evidence to determine whether acupuncture is effective for controlling menopausal vasomotor symptoms ⁵⁸⁾. When we compared acupuncture with sham acupuncture, there was no evidence of a significant difference in their effect on menopausal vasomotor symptoms. When we compared acupuncture with no treatment there appeared to be a benefit from acupuncture, but acupuncture appeared to be less effective than hormone therapy. These findings should be treated with great caution as the evidence was low or very low quality and the studies comparing acupuncture versus no treatment or hormone therapy were not controlled with sham acupuncture or placebo hormone therapy. Data on adverse effects were lacking.

Functional dyspepsia

A Cochrane Review ⁵⁹⁾ was done in 2014 to to assess the efficacy and safety of manual acupuncture and electroacupuncture in the treatment of functional dyspepsia. However, all the evidence was of low or very low quality. The body of evidence identified cannot yet permit a robust conclusion regarding the efficacy and safety of acupuncture for functional dyspepsia. It remains unknown whether manual acupuncture or electro-acupuncture is more effective or safer than other treatments for patients with functional dyspepsia.

Irritable bowel syndrome

Sham-controlled randomized controlled trials have found no benefits of acupuncture relative to a credible sham acupuncture control for IBS symptom severity or IBS-related quality of life ⁶⁰⁾. In comparative effectiveness Chinese trials, patients reported greater benefits from acupuncture than from two antispasmodic drugs (pinaverium bromide and trimebutine maleate), both of which have been shown to provide a modest benefit for IBS. Future trials may help clarify whether or not these reportedly greater benefits of acupuncture relative to pharmacological therapies are due entirely to patients’ preferences for acupuncture or greater expectations of improvement on acupuncture relative to drug therapy.

Stress urinary incontinence in adults

Stress urinary incontinence is a common disease among older people, especially women. The symptoms are leakage of urine when the person coughs, laughs or exercises. It affects social, psychological, physical and financial aspects of life.

The effect of acupuncture for stress urinary incontinence for adults is uncertain. There is not enough evidence to determine whether acupuncture is more effective than drug treatment ⁶¹⁾.

Schizophrenia

A 2014 Cochrane Review ⁶²⁾ found limited evidence suggesting that acupuncture may have some antipsychotic effects as measured on global and mental state with few adverse effects. Better designed large studies are needed to fully and fairly test the effects of acupuncture for people with schizophrenia.

Vascular dementia

The effectiveness of acupuncture for vascular dementia is uncertain ⁶³⁾. More evidence is required to show that vascular dementia can be treated effectively by acupuncture. There are no randomized controlled trials and high quality trials are few. Randomized double-blind placebo-controlled trials are urgently needed.

Acupuncture side effects

Acupuncture is generally considered safe when performed by an experienced, well-trained practitioner using sterile needles. Improperly performed acupuncture can cause serious side effects.

The U.S. Food and Drug Administration (FDA) regulates acupuncture needles as medical devices for use by licensed practitioners and requires that needles be manufactured and labeled according to certain standards. For example, the FDA requires that needles be sterile, nontoxic, and labeled for single use by qualified practitioners only.

Acupuncture in the developed parts of the world involves single-use, disposable needles packaged and sealed by the manufacturer in sterile conditions. Although case reports have highlighted major adverse events, such as organ puncture, infections, and bleeding complications, more recent, larger cohort studies using universal precautions have not found a significant complication rate. In a 2001 study of more than 34,000 acupuncture treatments in the United Kingdom, no serious adverse events (e.g, hospitalization, permanent disability, or death) were reported in relation to acupuncture therapy, and the rate of underlying minor adverse events (e.g, nausea, fainting, prolonged aggravation of existing symptoms, and psychological or emotional reaction) was reported to be between 0 and 1.1 per 10,000 treatments ⁶⁴⁾. Acupuncture involves puncturing the skin, and therefore slight bruising, bleeding, or soreness at the acupuncture site may occur because of needle penetration through capillaries. More serious adverse effects, such as a vasovagal response with a decrease in blood pressure and syncope, have been reported. Infections may occur at the needle site from the use of nonsterile needles. When herbs are burned too close to the skin, burn injuries can result around the needle site.

Acupuncture is generally considered safe for persons with bleeding disorders or taking anticoagulants. However, it is important for the patient to advise the practitioner of these facts so the practitioner can use vigilance in selecting insertion points. Acupuncture during pregnancy is a matter of continued debate. Certain acupuncture points are contraindicated because they may induce uterine contractions and premature labor.

What is snake gourd

Snake gourd (Trichosanthes cucumerina Linn.) commonly named as viper gourd, snake tomato, long tomato, padval or serpent, is long and curved fruit. The fruit is usually consumed as a vegetable due to its high nutritional value. Snake gourd fruit is usually divided into two different categories. There are the extremely long varieties that are grown for ornamental purposes and have hard skin and there are those grown for eating and medicinal purposes. These Snake gourds have a waxy green skin and are often speckled or striped with a lighter shade of green. The fruit is eaten when young. Longer varieties are best harvested when they are between 16 and 18 inches long. Smaller varieties are best harvested at 6 to 8 inches in length. When the gourd is young, the seeds are fairly nonexistent and the pulp around the seed mass is firm. The taste of a Snake gourd is similar to that of a cucumber. As a Snake gourd gets older, the rind gets hard and turns red. The taste becomes bitter and the insides gelatinous. The seeds are very hard and look similar to jagged-edged watermelon seeds.

Snake gourd is soft and bland and can be prepared and used like zucchini; sautéed and served as a side dish or added to dishes with other sautéed vegetables. Snake gourds can also be stuffed or sliced and grilled. In Asian dishes, Snake gourd is made into chutneys and pickled. When the gourd is mature, the seed mass within is scraped out and used like tomato paste in various Indian dishes. The shoots, tendrils, and leaves are also eaten as greens.

Studies on the pharmacological activities of Snake gourd have shown the presence of anti-inflammatory activity in root tubers ¹⁾, antidiabetic activity in seeds ²⁾, hepatoprotective activity in whole plant ³⁾, antidiabetic ⁴⁾, anti-inflammatory ⁵⁾, antioxidant ⁶⁾, antibacterial ⁷⁾, hypolipidaemic and antihyperglycemic activities ⁸⁾ in aerial parts, and cardioprotective activity ⁹⁾ in fruits of T. cucumerina. Recent scientific investigations have also shown significant gastroprotective activity in fruit seeds ¹⁰⁾ and aerial parts ¹¹⁾ of Snake gourd aqueous extracts. However, despite all these positive findings from animal and test tube studies, there is to date NO human studies to back up these findings/claims. Therefore, we must conclude that there is insufficient evidence to support the health claims or medicinal properties on Snake gourd. Human studies are desperately needed to support these findings.

Figure 1. Snake gourd

Snake gourd nutrition

Snake gourd is an annual climber belonging to the family Cucurbitaceae and commonly grown in Asian countries including Sri Lanka, India, Malaysia, Peninsula, and Philippines ¹²⁾. The plant is a rich source of functional constituents other than its basic nutrients such as flavonoids, carotenoids, phenolic acids, and soluble and insoluble dietary fibers and essential minerals, which makes the plant pharmacologically and therapeutically active ¹³⁾, ¹⁴⁾. The plant contains proteins, fat, fiber, carbohydrates, minerals, and vitamins A and E in high levels. The predominant mineral elements are potassium (121.6 mg/100 g) and phosphorus (135 mg/100 g) and also sodium, magnesium, and zinc are found in fairly high amounts ¹⁵⁾.

Snake gourd benefits

In Ayurveda and Siddha, the ancient medical system of India, the Snake gourd serves multiple purposes. Ingesting the fruit, leaves and flowers of the Snake gourd plant aided in digestive disorders, diabetes, skin diseases and general malaise. The root is used as a cure for bronchitis, headache and boils. Externally, the leaf juice is rubbed over the liver to relieve liver congestion. Both the root and fruit are considered to be cathartic. The fruit is used as an anthelmintic in French Guiana. The seeds are used for stomach disorders in Malabar Coast and is also considered antifebrile and anthelmintic. The aerial parts of Snake gourd are used along with other plant materials for indigestion, bilious fevers, boils, sores, skin eruptions such as urticaria, eczema, dermatitis, psoriasis diabetes and peptic ulcers ¹⁶⁾. In traditional Chinese medicine, Snake gourd is used for the treatment of cerebrovascular and cardiovascular diseases due to its various pharmacological activities, such as dispelling phlegm to relieve cough and chest stuffiness ¹⁷⁾. Snake gourd significant hypoglycemic, antioxidant, and immuno enhancing activities have been recently documented ¹⁸⁾. The whole plant including root, fruit, leaf, and seed have medical properties. Snake gourd has anti-inflammatory activity and antidiabetic activity ¹⁹⁾. In Sri Lanka, it is the aerial parts of Snake gourd that are used in the traditional medicinal system for treating disease conditions. Snake gourd is one of the major ingredients in several polyherbal preparations that are prescribed in Sri Lanka for the control of Diabetes Mellitus ²⁰⁾. In a study done by Arawwawala et al. ²¹⁾, the hot water extract of aerial parts of Snake gourd was found to significantly reduce the blood glucose levels and improve the glucose tolerance of normoglycemic and STZ-induced diabetic rats. In addition to this, Arawwawala et al. have done several studies on Sri Lankan Snake gourd and have reported it to show antioxidant ²²⁾, anti-inflammatory ²³⁾, antimicrobial ²⁴⁾, and gastroprotective ²⁵⁾ properties.

The chemical constituents present in Snake gourd are cucurbitacin B, cucurbitacin E, isocucurbitacin B, 23, 24 -dihydroisocucurbitacin B, 23,24-dihydrocucurbitacin E, sterols 2 β-sitosterol, stigmasterol, α-carotene and β-carotene that are reported to have antioxidant activity ²⁶⁾.

It has been reported that Snake gourd fruit pulp has the antioxidant activity ²⁷⁾. The aerial parts of Snake gourd plant have both hepatoprotective ²⁸⁾ and gastroprotective ²⁹⁾ activities. Furthermore, Snake gourd has also been used in the treatment of headache, alopecia, fever, abdominal tumors, bilious, boils, acute colic, diarrhea, haematuria, and skin allergy ³⁰⁾. Snake gourd is used as an abortifacient (causing abortion), vermifuge (destroy parasitic worms medicine), refrigerant, purgative, malaria, laxative, hemagglutinant (clumping together of red blood cells), emetic, cathartic, bronchitis, and anthelmintic. However, currently there are no human studies to validate any of the above claims, mentioned benefits or uses for the medical conditions.

What is dandelion tea

Dandelion (Taraxacum officinale) is a large genus of flowering plants in the family Asteraceae. The common name dandelion (from French dent-de-lion, meaning “lion’s tooth”) is given to members of the genus Asteraceae. Like other members of the Asteraceae family, they have very small flowers collected together into a composite flower head. Each single flower in a head is called a floret. Bees and other pollinating insects love dandelions. The flower heads consist of tube-like florets, each containing nectar and pollen. Dandelion is commonly regarded as a regular garden weed, but it has long been used in traditional Chinese medicine for ailments ranging from digestive disorders to complex disorders such as uterine, breast and lung tumors ¹⁾. Traditional Middle Eastern remedies require dandelions for spleen and liver ailments, while Native Americans have harnessed their properties to cure indigestion, heartburn, and kidney disease ²⁾, ³⁾. Dandelion plants were used by East Indians in the 16 century as a hepatic stimulant, diuretic, for liver disorders, and most interestingly, for chronic skin diseases ⁴⁾. These roots are a source of triterpenes and steroids ⁵⁾. Hata et al. ⁶⁾ found that upon screening a variety of compounds from wild plants, Dandelion (Taraxacum officinale) was an effective inducer of differentiation in mouse melanoma cells. Furthermore, this group found that one constituent of Chinese dandelion, Lupeol-a triterpene, up-regulated melanogenesis and decreased cell proliferation in mouse melanoma ⁷⁾. This triterpene is regarded as cytostatic and not cytotoxic. In another study, skin tumours were promoted in vivo in mice through a two-stage chemical carcinogenesis and treated with water and methanol extracts of Taraxacum japonicum. This showed inhibition of tumor initiation and promotion at both carcinogenesis stages, and it was concluded that Taraxacum, and more specifically taraxasterol (a triterpenoid), is a worthy chemopreventative agent ⁸⁾.

Figure 1. Dandelion

What is dandelion tea good for

Dandelion extracts have been used for centuries for traditional Chinese medicine and native American medicine to treat cancers, hepatitis, and digestive diseases ⁹⁾, ¹⁰⁾. In Taiwan as well as mainland China, Dandelion is commonly known as herbal tea, is a popular folk drink with a number of functional ingredients and traditionally used by herbalists and doctors for the treatment of boils, sores, inflammation of the eye, urethral infection, lung and breast abscesses, acute appendicitis and jaundice ¹¹⁾. A whole plant extract of Dandelion has been found to have antibacterial, antifungal, antileptospiral, and antiviral effects, all of which have been reported by previously studies ¹²⁾, ¹³⁾, ¹⁴⁾.

Components of Dandelion root extract include sesquiterpenes (derivatives of germacranolide, eudesmanolide, and guaianolide), different triterpenes like taraxasterol—their hydroxy derivatives and their acetates—phenolics compounds (such as chicoric acid, vanillic acid, p-hydroxyphenylacetic acid, p-hydroxybenzoic acid, syringic acid, caffeic acid, chlorogenic acid, and ferulic acid), and coumarins (scopoletin, esculetin, and umbelliferone) ¹⁵⁾. Dandelion extracts are shown to have anti-inflammatory, antioxidant, and anticarcinogenic activities; however, there has been little scientific advancement made in this field with regard to the effect of dandelion root extract on cancer. Scientists are yet to determine the effect of each of the individual components (such as the family of triterpene alcohols and phenolic acids—found in the Dandelion roots—and cinnamic acids, flavinoids and coumarins—that are found in the leaves) ¹⁶⁾ but they believe that the compounds in dandelion root extract most likely work in synergy with each other to produce the anti-inflammatory, antioxidant, and anticarcinogenic effect.

Jeon et al. ¹⁷⁾ have shown that ethanolic dandelion extracts antioxidant activity by reducing levels of reactive oxygen species (ROS) and nitric oxide production (NO) and inhibit COX-2 expression, thus making dandelion extracts not only anti-carcinogenic, but anti-inflammatory, antiangiogenic and also antinociceptive. Dandelion flower extracts were tested on RAW264.7 cells (mouse macrophages) and exhibited inhibition of nitric oxide production in these noncancerous cells. The inhibition of reactive nitrogen species (RNS) as well as reactive oxygen species (ROS) by dandelion flower extracts was attributed to its phenolic components ¹⁸⁾. Sigstedt et al. tested aqueous dandelion flower extract, dandelion leaf extract and dandelion root extract, on a variant MCF-7 breast cancer cell line (MCF-7/AZ) and LNCaP prostate cancer line. While dandelion leaf extract inhibited cell proliferation in MCF-7/AZ, dandelion flower extract and dandelion root extract did not. However, dandelion root extract and dandelion leaf extract blocked invasion of MCF-7/AZ and LNCaP cells (into collagen type I), respectively. Inhibition of cell invasion was corroborated by reduced matrix metalloproteinase activity of MMP-2 and -9, as well as reduced phosphorylation levels of src and FAK ¹⁹⁾. Dandelion extract was used to treat Hep G2 human hepatoma cells and was found to reduce cell viability and induce cytotoxicity through interleukin-α and TNF-α ²⁰⁾. Regardless of the valuable traditional knowledge of dandelion antitumor activity, there has been inadequate biochemical research to apply this knowledge to cancer cell lines and especially chemo-resistant melanoma.

In another study, Choi et al. ²¹⁾ reported hypolipidemic effects of dandelion leaf (1 % w/w) in rabbits fed with a high-cholesterol diet. They reported an improvement on lipid profile (-36 % on triglycerides, -11 % on LDL values, and 29 % higher of HDL concentration) of treated rabbits compared with the control. A group of twenty eight male rabbits was divided into four subgroups; a normal diet group, a high-cholesterol diet group, a high-cholesterol diet with 1% (w/w) dandelion leaf group, and a high-cholesterol diet with 1% (w/w) dandelion root group. After the treatment period, the plasma antioxidant enzymes and lipid profiles were determined. The results of that study show that treatment with dandelion root and leaf positively changed plasma antioxidant enzyme activities and lipid profiles in cholesterol-fed rabbits, and thus may have potential hypolipidemic and antioxidant effects ²²⁾. However there is no human trial that showed similar positive outcome either for lowering cholesterol, weight loss (body and fat loss) or on antioxidant effects.

In both Traditional Chinese Medicine and in Ayurvedic medicine, dandelion leaf in various preparations including infusions, ethanolic extracts, or fresh expressed juice were used to enhance urinary output or diuresis ²³⁾. Supporting this indication, the German Standard License for dandelion tea includes stimulation of diuresis and the German Commission E approves the use of dandelion for diuresis ²⁴⁾. Rácz-Kotilla et al. ²⁵⁾ quantified the diuretic activity in a mice model, reporting that the leaf of dandelion, a better diuretic and saluretic (promotes excretion of salt) than the dandelion root, was comparable to furosemide (Lasix at 80 mg/kg). Despite consistent traditional use, a recent review article by Schutz et al. ²⁶⁾ discusses the mixed results and scant data of the pharmacological research characterizing dandelion’s utility as a diuretic. Moreover, these results do not rule out that dandelion leaf acts as a bladder irritant due to the increase in the daily frequency but not the daily urination volume ²⁷⁾. Furthermore, other investigations utilizing mice models have failed to find increases in daily urination volume. Tita et al. ²⁸⁾ observed no diuresis over 2 hours after a single unspecified dose. Hook et al. ²⁹⁾ also using a single dose over a few hours, observed a saluresis (urinary excretion of salt), but not increased production of urine. These results suggest further detailed investigations are warranted.