An excellent source of essential fatty acids, this herb show promise in benefiting conditions ranging from PMS to high cholesterol, hypertension and cancer.

Evening primrose (Oenothera biennis), a native of North America, was brought to Europe in the 17th century. The plant is biennial, and in its first year produces many oblanceolate leaves that spread flat near the ground. In its second year, a hairy stem grows to a height of about 3–4 feet. In mid-summer the blooming plants produce large yellow flowers that are followed by downy pods containing small seeds. Evening primrose is commonly found in old fields, ditches, and waste places.¹

This herb has been used for a wide range of problems. Native Americans consumed the leaves, roots, and seedpods as food and prepared extracts for use as a painkiller and asthma treatment.² Modern uses include treatment for rheumatoid arthritis, eczema, multiple sclerosis, premenstrual syndrome (PMS), cardiovascular disorders, chronic fatigue syndrome, Raynaud’s syndrome, weight loss, and diabetes. Herbalists mainly use the flowers and the seeds. The oil from this plant is high in gamma-linolenic acid (GLA) and essential polyunsaturated fatty acid, which is converted into prostaglandins, hormones necessary for many body functions. The medicinal uses of the oil rely on the wide variety of effects of the high essential fatty acid content cis-linoleic acid (LA, n-6) and especially of cis-gamma-linolenic acid (GLA, n-6). The freshly pressed oil from the seeds is light yellow, having at least 85%–92% unsaturated fatty acids. Most of the polyunsaturated fatty acids are comprised of the essential LA and the rare GLA forms. Depending on the brand, the oil contains a minimum of 8%–12% GLA. The highly unsaturated oil is perishable and rancidifies shortly after preparation. Natural antioxidants like vitamin E preserve and stabilize the oil in its biologically active cis conformation.³

Studies have shown that evening primrose oil can help lower blood cholesterol and blood pressure; treat symptoms of PMS, alleviate anxiety; and possibly help schizophrenic patients. This herb is an old remedy for infantile eczema or “cradle cap”; moreover, adults with atopic eczema showed improvement after being treated with evening primrose oil (EPO).³

Chemical Composition & Pharmacology
Although evening primrose is mainly used for its high content of essential fatty acids, this plant contains additional medicinally active ingredients. One component, a member of the triterpene family, alpha-amyrin and its palmitate and linoleate esters, tested positively in induced arthritis and cancer models. When compared with the anti-arthritic drugs indomethacin and methotrexate, amyrin esters caused considerable reduction in carrageenin-induced rat pedal edema. They were also very effective in reducing osteosarcoma cell growth.⁴ A number of phenolic compounds and their derivatives were isolated from the leaves. A representative member of the family, caffeic acid, has many pharmacological actions. In general, naturally occurring phenolic acid compounds showed anti-apoptotic effect in vitro. Apoptosis induced on endothelial cell culture by oxidized low-density lipoproteins (LDL) using caffeic acid prevented cell death in a dose-dependent manner.⁵ Caffeic acid also showed a neuroprotective effect by inhibiting 5-lipoxygenase activity. The increased activity or expression of the 5-LO enzyme has been associated with age-related neurodegenerative processes.⁶ A triterpene fraction of seeds contains cycloartenol, whose anti-inflammatory activity has been tested against carrageenan-induced edema in rats.⁷ In a mouse experiment, cycloartenol inhibited peritoneal leukocyte infiltration, in a dose-dependent manner, and also showed a weak inhibition of phospholipase A₂ under in vitro conditions.⁷

Other components isolated from the leaves include delphinidin, ellagic acid, gallic acid, kaempferol coumaric acid, and quercetin. Delphinidin, an anthocyanin, prevents endothelial cell injury associated with oxidative stress.⁸ Ellagic acid has been reported to be an effective chemopreventive agent and to inhibit chemically induced cancer in the lung, liver, skin, and esophagus of rodents.⁹ Ellagic acid with other polyphenols has been identified as a potent inhibitor of human topoisomerase I and II.¹⁰ Gallic acid has been shown, together with the alkyl derivatives, to inhibit tumor proliferation. Gallic acid and alkyl derivatives are used as antioxidant food additives.¹¹

Evening primrose oil, prepared from the seeds, contains high levels of gammalinolenic acid (GLA), which is essential for the synthesis of other polyunsaturated fatty acids. These fatty acids are important building blocks for phospholipids, as well as precursors for prostaglandin synthesis (FIGURE 1).

Clinical Studies and Therapeutic Actions
In human liver cells, desaturases can introduce double bonds at the delta-9 positions of fatty acids but cannot introduce additional double bonds in the carbon chain between C-10 or the methyl end of the chain. Plants contain the desaturases that can introduce double bonds at delta-12 and delta-15 positions. Therefore, linoleate (18:2 delta-9,-12) and a-linolenate (18:3 delta-9,-12,-15) are essential to human consumption in order to synthesize additional series of polyunsaturated fatty acids and prostaglandins. Two enzymes, delta-6 and delta-5 desaturases, have a crucial role in introducing double bonds in the carbon chain; their expression and activity decline with age. An outline of essential fatty acids (EFA) and PG metabolism is shown in FIGURE 1. Deficiency of these EFAs can lead to different symptoms and chronic diseases.

PMS: Recent theories about the causes of PMS include hormonal imbalances involving estrogen-progesterone, pyridoxine (vitamin B₆) deficiency, elevated serum aldosterone, hypoglycemia, abnormal magnesium metabolism, and varying prostaglandin (PG) levels in the female reproductive tract.12-14 Prostaglandin series-1 derives from dihomogammalinolenic acid (DGLA) while the better-known PG-2 series derives from arachidonic acid. In adults the delta-5-desaturase had little of the activity that converts DGLA to arachidonic acid.¹⁵ Therefore, most of the arachidonic acid used for PG-2 synthesis should come from the diet, especially from meat and dairy products. Administering the precursor gamma-linolenic acid is an obvious choice in order to enhance synthesis of the PG-1 series. A study conducted in a London hospital using Efamol (primrose oil as a source of gammalinolenic acid) involved 68 women who had failed to respond to other therapeutic regimens. Of these women, 61% experienced total remission and 23% experienced partial remission. The dosage of Efamol (0.5 g/capsule), originally twice a day in the luteal phase, was gradually increased to four capsules, twice a day, during the whole cycle for 18 months. Only a few patients complained of side effects and those symptoms were not necessarily related to Efamol. In Helsinki, Finland, in a double-blind placebo-controlled study, patients were treated with Efamol for four cycles. These patients had not been treated with drugs before the experiment. Efamol showed a 40% average improvement in parameters tested, especially in irritability and depression.¹⁵ In an English study, 196 women who were scored one cycle before Efamol treatment were treated with two Efamol capsules morning and evening during the luteal phase. These women showed significant (p < 0.001) improvement in all five symptoms tested (irritability, depression, breast pain and tenderness, headache, and ankle swelling).¹⁵ Although results of smaller-scale studies showed improvement in symptoms, differences were not significant compared to placebo.¹⁶

Treatment for Mastalgia: Breast pain requires a thorough look into the patient’s history, and a physical and radiological evaluation, which can be used to exclude breast cancer. In many cases, simple therapy (a well-fitting bra, a decrease of dietary fat, discontinuing oral contraceptives or hormone replacement therapy) can help. In addition to the prescription Danazol, evening primrose oil is often included in the pharmacological therapy.¹⁷ In a multiple-randomized drug study, 291 women with severe breast pain (cancer excluded) obtained good results with evening primrose oil treatment. Forty-five percent of patients who were treated with six capsules per day for three to six months responded positively.¹⁸

Atopic Eczema: Atopic eczema might be related to abnormal EFA metabolism; an imbalance in the two EFAs in the plasma phospholipids has been shown. Linoleic acid level is somewhat higher than normal, and gammalinolenic acid and its derivatives are reduced.^19-21 A meta-analysis of 9 controlled trials of EPO therapy that assessed the severity for eczema by scoring measures of inflammation, dryness, scaliness, and overall skin improvement showed a highly significant improvement (p < 0.0001) in patient and doctor scores over baseline as a result of primrose oil treatment.²¹ A positive correlation was found between improved clinical condition and plasma levels of DGLA and arachidonic acid (AA). The rise of DGLA was expressed more than AA alone, indicating that DGLA conversion to AA is slow, with 5-desaturase enzyme activity the limiting factor. The limited access of AA in the plasma did not result in increased production of AA-derived eicosanoids. To the contrary, Epogam treatment reduced inflammation. The authors suggested that AA was conserved in skin phospholipid and other lipid fractions rather than used for prostaglandin synthesis.
Rheumatoid Arthritis: A double-blind, placebo-controlled study was carried out for 24 weeks with 37 arthritis patients treated with 1.4 g/day GLA or cottonseed oil (placebo). Joint tenderness and swelling, morning stiffness, grip strength, and ability to perform daily activities were evaluated. Treatment with gammalinolenic acid reduced the signs and symptoms of the disease significantly in all four parameters (p < 0.05), while patients receiving placebo had no significant improvement. No side effects were registered with the applied doses.²² Earlier, in a similar study using borage oil as a source of GLA for 12 weeks at 1.1 g/day, GLA administration appeared to reduce synovitis in six out of seven patients with rheumatoid arthritis.²³

Lowering Plasma Cholesterol: It is generally accepted that polyunsaturated fatty acid (PUFA) intake lowers plasma cholesterol levels. Clinical studies successfully applied different plant oils, containing EFAs, in the diet. In a combined clinical trial for 12 weeks in England, 84 patients received either primrose oil or placebo; 12 patients were treated for hyperlipidemia and/or hypertension and received Efamol (6–8, 0.5 g capsules/day for at least 12 weeks; and the remaining patients, aged 15–69, were assigned to a placebo-controlled, double-blind crossover study.²⁴ They were randomly assigned to receive 4, 8, or 12 capsules containing 0.5 g of primrose oil (GLA content 9%). Total cholesterol level was measured in all of the patients, and in 54 patients HDL and LDL cholesterol levels were measured separately. Evening primrose oil treatment showed a significant (p < 0.0001)
cholesterol-lowering effect in patients with plasma cholesterol levels above 5 mmol/L. Patients with the highest total cholesterol levels had a decrease of 30%. The cholesterol-lowering action reduced LDL level, shifting the ratio of LDL/HDL from 3.2 to 2.38.²⁴ Other studies with fewer patients obtained mixed results on the effectiveness of EPO in lowering cholesterol. The effect of dietary oils rich in oleic, linoleic and linolenic acid were studied in eight normolipidemic men; the mean plasma cholesterol level dropped 18% while LDL decreased 22%.²⁵

Diabetes: Both in human and experimental diabetes mellitus cases, a substantial disturbance of the metabolism of n-6 essential fatty acids has been observed. The conversions of dietary linoleic acid to gamma-linolenic, dihomogammalinolenic, and arachidonic acids are inadequate,²⁶ leading to an imbalance in the synthesis of prostaglandin series I and II. This causes a variety of microvascular abnormalities. The escalating situation leads to further reduced blood flow, hypoxia, and cellular damage.26 Arisaka and coworkers demonstrated that patients with type 1 diabetes mellitus have decreased serum levels of dihomogammalinolenic acid and arachidonic acid along with elevated plasma levels of PGE₂ and PGF_2alpha. They completed a clinical study of 11 children with type 1 diabetes mellitus, to assess the effect of dietary supplementation of gammalinolenic acid. In this double-blind, placebo-controlled study, EPO (containing 45 mg GLA and 360 mg LA) was given for 8 months, initially 2 capsules/day for 4 months and 4 capsules/day for the rest of the study. Four capsules daily increased DGLA levels and significantly decreased PGE₂ (p < 0.01) compared to placebo. The researchers concluded that altered EPO and PG metabolism in diabetes may be reversed by GLA supplementation.²⁷ EPO, in combination with fish oil and vitamin E, was studied in patients with type 2 diabetes as well. Seven patients were administered 4 g of EPO, 2.4 g of sardine oil, and 200 mg of vitamin E for 4 weeks. Fasting plasma glucose, hemoglobin A1c, total cholesterol, body weight, and percentage of body fat mass were decreased as a result of the treatment but did not significantly differ from placebo. In the treatment group, eicosapentaenoic acid (20:5) increased in all lipoprotein fractions, but DGLA increased only in HDL. The treatment also resulted in a decrease of 11-dehydrothromboxane B2 excretion, measured in urine (32.7%; p < 0.05), but did not influence plasma PGE1 or 6-ketoPGF1alpha. The result showed that the combination of essential oils is useful in improving abnormal lipid and thromboxane A₂ (TXA₂) metabolism in diabetic patients.²⁸

Multiple Sclerosis: Some studies have shown an improvement in MS patients whose diet was supplemented with EFAs. MS is associated with abnormalities in EFA metabolism and lymphocyte function.²⁹ Patients with MS have low EFAs in their blood cells, a deficiency in PGE1 synthesis and abnormal activation of T lymphocytes against self proteins. Although a primrose oil- or linolenic acid-rich diet improved symptoms of some patients, it was more effective in combination with colchicine. In France, the effects of EPO were studied on platelets of MS patients. While there was not a significant effect on platelets, thrombin-induced platelet aggregation was higher in MS patients after oil treatment.³⁰ It is too early to conclude that MS patients cannot be helped by EPO treatment. Most studies suggest that combined drug therapy including EPO may benefit MS patients.

Cancer: Malignant cell growth is a well studied but not fully understood multifactorial process. Most studies were carried out in vitro. Cancer cells in culture have a number of common characteristics: they exhibit aerobic glycolysis, fail to show feedback regulation of cholesterol biosynthesis, do not regulate cytoplasmic Ca²⁺ levels normally, and produce excessive amounts of PG series-2. These transformed cells also cannot synthesize PGE1 because of loss of delta-6 desaturase.³¹ It has been suggested that restoration of the synthesis or supplementing PG series 1 and 2 may be a critical step in normalizing cellular functions and reversing cancer growth.³² Unsaturated fatty acids of the n-6 and n-3 class have been shown to affect tumor growth and metastasis. Eicosapentaenoic acid (20:5, n-3) and docosahexaenoic acid (22:6, n-3) have an inhibiting effect on tumor growth.³³ While most of the in vitro experiments controlling cancer cell growth by GLA succeeded, there is very little evidence that they worked in vivo. This is not surprising, since a well-controlled in vitro cell culture differs from the whole body condition. Just a few reasons why the in vivo experiments could fail are that EPO can be taken up much less by tumor cells than by the cells in culture; that tumor cells in the body have free access to other precursors that have been restricted in cell culture; that tumor cells may have developed selective absorption in vivo; or that tumor cells may have different cell-cell communications in a mixed population while apoptotic signal transduction does not work. These hypotheses demonstrate the difficulty of transition from cellular experiments to whole body complexity. Nevertheless, there are many promising animal and human data to support the effectiveness of EPO dietary intervention in breast cysts and tumors.^34-36

Dosage and Side Effects: The recommended daily dosage of EPO for adults does not exceed 4 g (containing ~300–360 mg GLA). In some cases, such as atopic eczema, the dosage could temporarily be higher, i.e., 4–8 g/day. For children, the advisable dose is 2–4 g/day. Both LA and GLA are present in breast milk. A breast-fed baby consumes 23–65 mg GLA/kg/day; therefore, to provide sufficient amounts of EFA for both the mother and the baby, EPO may be taken during pregnancy and while breast-feeding. Adverse effects are rare at recommended dosages. Fewer than 2% of people using the oil on a long-term basis experienced mild GI effects (indigestion, nausea, softening of stools) and headaches.³⁷ No toxic effects have been observed even at high dosages (5 mL/kg/day). The only side effects reported were possible worsening of temporal lobe epilepsy or schizophrenia if administered with conventional drug therapy. Therefore, it is contraindicated when patients are taking epiloptogenic drugs such as phenothiazines.^37-39

Conclusion
The loss of activity and expression of delta-5 and delta-6 desaturases with aging stresses the importance of supplementing diets with EFAs to avoid deficiency, metabolic complications or diseases. A strong correlation between aging and a rapid fall of delta-6 desaturase levels has been shown in the testes and liver in rats.⁴⁰ Food restriction, as well as aging, can reverse the decrease in expression of delta-6 desaturase. Supplementing the diet with EFAs from sources such as evening primrose, borage, flaxseed oil, and fish oil may prevent several diseases. To enhance the benefits of EFAs, a regimen of supplements, such as zinc, vitamin B₆, vitamin B₃, and vitamin C, should be taken. These supplements are important regulating factors of the delta-6-desaturase enzyme.

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