Evening primrose oil

Evening Primrose Oil (Oenothera biennis)

1. Identity: Botanical and Chemical Classification

Plant Source and Taxonomy

Evening primrose (Oenothera biennis L.) is a species of flowering plant in the family Onagraceae, native to eastern and central North America, from Newfoundland west to Alberta, southeast to Florida, and southwest to Texas, and widely naturalized elsewhere in temperate and subtropical regions. It usually has a life span of two years (biennial), growing to 1.6 m (5 ft 3 in) tall in the seeding year. The plant, now also grown throughout Europe and parts of Asia, has yellow flowers that open at sunset and close during the day.

Other common names include evening star, sundrop, weedy evening primrose, German rampion, hog weed, King's cure-all, and fever-plant. Etymologically, Oenothera means "a soporific plant," and biennis refers to its biennial life cycle. Oenothera biennis L. is the primary commercial source of evening primrose oil.

Extraction and Preparation

Evening primrose oil (EPO) is obtained by cold expression or solvent extraction from the seeds of the evening primrose plant. Evening primrose oil is generally obtained by mechanical pressing, followed by extraction with hexane. The cold-pressed method avoids chemical solvents and is considered the premium commercial standard for dietary supplements.

Commercial Forms

Evening primrose oil is available in multiple preparations for both internal and external use. For dietary supplementation, softgel capsules are the most prevalent form, typically standardized to a known GLA content. Evening primrose oil may also be included in products that are applied to the skin, and it has been used orally (by mouth) or vaginally to attempt to get labor started at the end of pregnancy. The oil is also incorporated into cosmetic formulations including face creams, serums, and moisturizers.

2. Key Constituents and Chemical Composition

Primary Fatty Acid Profile

It is believed that the most interesting sources of biologically active compounds are the seeds and, above all, evening primrose seed oil. This oil contains mainly aliphatic alcohols, fatty acids, sterols, and polyphenols. Evening primrose oil (EPO) is extremely high in linoleic acid (LA) (70–74%) and γ-linolenic acid (GLA) (8–10%), which may contribute to the proper functioning of human tissues because they are precursors of anti-inflammatory eicosanoids.

The oil consists of triacylglycerols — about 98% — with a small amount of other lipids and about 1–2% non-saponifiable fraction. GLA [C18:3Δ6,9,12] is an unsaturated fatty acid in demand for its nutritional and pharmaceutical applications.

Secondary Phytochemicals in Other Plant Parts

The aqueous leaf extract of Oenothera biennis contains phenolic compounds (e.g., ellagitannins and caffeoyl tartaric acid) and flavonoids (quercetin glucuronide and kaempferol glucuronide). Among the tannins contained in the leaves of the evening primrose are oenothein A and oenothein B.

The roots of evening primrose contain the following sterols: sitosterol, oenotheralanosterol A, and oenotheralanosterol B. The triterpenes maslinic acid and oleanolic acid are also present in the root. The following tannins are also found: gallic acid, tetramethylellagic acid, oenostacin, and 2,7,8-trimethylellagic acid.

The plants of this genus are a botanical source for various pharmaceutically active components like sterols, alkaloids, phenolic acids, flavonoids, triterpenoids, saponins, biflavonols, and tocopherols.

3. Mechanisms of Action

The GLA → DGLA Metabolic Pathway

Linoleic acid is converted to GLA (18:3, n-6) by the action of the enzyme delta-6-desaturase, and GLA is elongated into the DGLA form (20:3, n-3), the precursor of prostaglandin H1 (PGH1), which in turn forms PGE1 and thromboxane A1 (TXA1). DGLA is also converted to arachidonic acid (AA) (20:4, n-6) by the action of the enzyme delta-5-desaturase. AA forms the precursor of PGE2, thromboxane A2 (TXA2), and leukotriene B4 (LTB4).

GLA is an important precursor of DGLA, which is itself a precursor of anti-inflammatory eicosanoids. It has been shown that GLA or DGLA supplementation causes a modest increase in the prostaglandin E1 (PGE1) level in tissues in relation to PGE2, but the biological properties of PGE1 are about 20 times stronger in comparison to PGE2. However, GLA or DGLA supplementation may cause their conversion to AA and pro-inflammatory eicosanoids. Therefore, it is suggested that the metabolism should be directed to anti-inflammatory eicosanoids.

GLA is rapidly converted in the body to DGLA, which is the precursor of Prostaglandin H1 (PGH1) that produces anti-inflammatory substances, PGE1, and thromboxane A1 (TXA1). PGE1 has anti-inflammatory, anti-coagulative, and vasodilator functions, and TXA1 regulates the pro-inflammatory characteristics of thromboxane A2 (TXA2).

Unlike other eicosanoids, DGLA cannot yield leukotrienes; however, it can inhibit the formation of proinflammatory leukotrienes from AA. Interestingly, GLA also has an antibacterial effect. In particular, it shows bactericidal activity against Staphylococcus aureus colonization on the skin, which is a common problem in atopic dermatitis patients.

Relevance to Delta-6-Desaturase Deficiency

At least in a subset of patients with atopic dermatitis (AD), a malfunction of delta-6-desaturase appears to play a pathogenetic role. This enzyme is responsible for the conversion of linoleic acid (LA) to gamma-linolenic acid (GLA), which is further metabolized to dihomo-gamma-linolenic acid (DGLA). DGLA is the precursor of prostaglandin E1 (PGE1) or 15-hydroxyeicosatrienoic acid (15-HETrE). As a result of reduced enzyme activity of delta-6-desaturase, high levels of LA and low levels of GLA have been observed in AD patients. Accordingly, less DGLA and its metabolites PGE1 and 15-HETrE, which have anti-inflammatory capacity, are produced.

When GLA is supplemented to atopic dermatitis patients through EPO, the GLA may bypass delta-6-desaturase, the rate-limiting enzyme, and directly enter the LA metabolic pathway, thereby gradually recovering the anti-inflammatory PGE1.

EPO supplementation results in an increase in plasma levels of γ-linolenic acid and its metabolite dihomo-γ-linolenic acid (DGLA).

In vitro, evening primrose oil demonstrates anti-inflammatory activity and inhibits platelet aggregation. In animal models, it exerts anti-angiogenic, anti-inflammatory, and anti-arthritic effects, and improved cardiac recovery after myocardial infarction.

4. Traditional and Historical Use

Native American Traditions

Native Americans applied juices from the plant's stem and leaves to the skin to treat skin inflammation, bruises, and minor wounds, and they used the leaves orally for gastrointestinal disorders and sore throats. The Cherokee, Iroquois, Ojibwas, and Potawatomi were among several Native American tribes that used evening primrose for both food and for medicinal purposes. They ate the cooked greens when young, and made a tea for overfatness and hot root poultice for piles.

Native Americans used the leaves and bark of evening primrose as a sedative and astringent; it was given for stomach and liver complaints as well as disorders of the female reproductive system. The bark and leaves are astringent and sedative and are used for the treatment of gastrointestinal disorders, whooping cough, and asthma.

Anishinaabe tribes traditionally make tea from the evening primrose leaves for use as a dietary aid and to reduce fatigue. The whole plant and especially the leaves are traditionally boiled to tea by Anishinaabe tribes as an energy stimulant and to facilitate weight loss.

Introduction to Europe

Evening primrose is indigenous to North America, although it was naturalized in the Mediterranean region when it was brought to Europe in 1619. Once established in Europe, the plant acquired a popular reputation as a cure-all. The English herbalist John Parkinson (1567–1650) described the use of evening primrose in 1629. European herbalists of the 17th century reportedly used various parts of the plant for conditions ranging from skin complaints to systemic ailments.

Food Uses

The leaves can be eaten raw in salads or cooked like spinach or in soups. Raw roots can be minced and marinated in salad vinaigrette before use in salad. When eaten raw, the roots are similar to radish. When cooked, the taste is similar to a turnip.

5. Scientific Evidence by Area of Use

5.1 Atopic Dermatitis (Eczema)

Atopic dermatitis (AD) has been one of the most extensively studied indications for EPO, with the biochemical rationale resting on the delta-6-desaturase hypothesis. A defect in the function of the enzyme delta-6-desaturase has been discussed as a major factor in the development of atopic eczema. Delta-6-desaturase is responsible for the conversion of linoleic acid to gamma linolenic acid. Several plants, including evening primrose, are known to be fairly rich in gamma linolenic acid. Hence, substitution of gamma linolenic acid in patients prone to developing atopic eczema seemed a feasible concept.

Early clinical trials showed promise. In a double-blind trial, patients with atopic eczema received either oral evening primrose oil (EPO) (n = 14) or placebo (n = 11) for 12 weeks. In the EPO group a statistically significant improvement was observed in the overall severity and grade of inflammation and in the percentage of the body surface involved by eczema as well as in dryness and itch. Patients in the placebo group showed a significant reduction in inflammation. The patients receiving EPO showed a significantly greater reduction in inflammation than those receiving placebo.

However, larger and better-controlled investigations have been less favorable. A Cochrane systematic review found no evidence that either borage oil or EPO are effective in treatment of eczema. Both products and the placebos used in the studies had similar mild, temporary side-effects, which were mainly gastrointestinal. The review included 27 studies with 1,596 adults and children from 12 countries; of these, 19 studies compared EPO with a placebo treatment and 8 used borage oil compared with placebo. Researchers looked for evidence of overall improvement in eczema and quality of life.

Although data could not be pooled because of differences between study participants, GLA doses, and outcomes (which were often clinically meaningless), the largest and best-reported studies did not show convincing evidence of any benefit. One randomized controlled trial of 151 people with atopic dermatitis specifically tested high-dose GLA capsules and found no statistically significant benefit for GLA supplementation compared with placebo (liquid paraffin or olive oil).

The current evidence suggests that oral evening primrose oil does not provide clinically significant improvement in persons with atopic dermatitis. However, most trials to date have significant methodologic flaws and must be considered preliminary.

One positive, smaller trial from India found that at the end of the fifth month, 24 (96%) patients of the EPO group and 8 (32%) patients of the placebo group showed improvement, with a significant difference in outcome between the two groups (P < 0.00001). No significant adverse effect was reported by any patient or guardian at any point of assessment. This study was, however, limited by small sample size and single-center design.

One open study with 21 patients investigated whether EPO supplementation results in an increase in plasma GLA and its metabolite DGLA, correlating with clinical improvement of AD assessed by the SCORAD index. EPO (4–6 g) was administered daily for 12 weeks. Before treatment, and 4 and 12 weeks after initiation of EPO supplementation, objective SCORAD was assessed and plasma concentrations of GLA and DGLA were determined by gas chromatography. A significant increase in plasma GLA and DGLA levels and a decrease in the objective SCORAD were observed 4 and 12 weeks after initiation of EPO treatment.

Overall, the weight of evidence from systematic reviews — particularly the 2013 Cochrane review — does not support the routine use of oral EPO for atopic dermatitis.

5.2 Mastalgia (Breast Pain)

Mastalgia, particularly the cyclical form, has been one of the most studied women's health indications for EPO. The rationale is that women with breast pain have low levels of GLA and its metabolite; thus, treatment with EPO was proposed to raise the levels of GLA and its metabolites towards normal and thereby relieve breast pain.

Early trials showed EPO to be useful for treating mild cases of cyclical mastalgia. Patient acceptance is high as it is viewed as a "natural substance" rather than a hormone or drug. The trials also suggested that non-cyclical pain is unresponsive to this therapy.

A systematic review and meta-analysis specifically evaluating EPO for mastalgia identified 13 trials with 1,752 randomized patients. Thirteen trials with 1,752 randomised patients were included. The results showed that EPO has no difference in reducing breast pain compared to topical NSAIDs, danazol, or vitamin E. The number of patients who achieved pain relief was no different compared to the placebo or other treatments.

The NCCIH concludes that evening primrose oil is probably not more effective than a placebo for breast pain. Some data indicate that supplementation with vitamin E and evening primrose oil reduced cyclical mastalgia, but other analyses did not find improvements in breast pain or premenstrual syndrome.

5.3 Premenstrual Syndrome (PMS)

PMS supplementation with EPO is suggested owing to PGE1's positive effect on abnormal sensitivity to the prolactin level in blood circulation in patients with PMS. Clinical trial results, however, have been inconsistent. In one trial, EPO significantly changed the PMS severity scores after the intervention, while no significant difference was observed in PMS scores after treatment with placebo. The symptom severity scores reduced from 53.2 ± 14.31 to 33.62 ± 16.94 after three months of administration of evening primrose oil, while these amounts were 53.38 ± 13.93 and 50.27 ± 16.94 in the placebo group, showing a significant difference between groups (P < 0.001).

A clinical trial with 38 patients tested oral EPO capsules for 6 months. The findings revealed that there were no advantages in EPO consumption in comparison with the placebo. It appears that EPO might not be effective in reducing PMS symptoms. The NCCIH states there is insufficient evidence to show whether evening primrose oil is helpful for PMS.

5.4 Menopausal Symptoms (Hot Flashes)

A meta-analysis including six randomized controlled trials (RCTs) found that the meta-analysis of 450 women revealed that women in the EPO group experienced a mean decrease of 2.13 in the number of hot flashes per day compared to the control group. EPO prescribed as 500 mg daily for 6 weeks for menopausal hot flashes was shown to reduce hot flashes significantly compared to placebo. It was assessed by the Hot Flash Related Daily Interference Scale questionnaire.

One study of 56 menopausal women concluded that evening primrose oil "offers no benefit," although another trial with the same number of women found that evening primrose oil makes hot flashes less intense. The evidence for menopausal hot flash reduction therefore remains mixed, and findings vary across individual trials.

5.5 Rheumatoid Arthritis

In rheumatoid arthritis, mixed results were observed, with some studies reporting significant improvements in symptoms while others found no significant impact. Preliminary data suggest benefit in some rheumatoid arthritis symptoms, but the evidence remains early-stage. The NCCIH states there is insufficient evidence to show whether evening primrose oil is helpful for rheumatoid arthritis. Overall, the evidence base for this indication is characterized as preliminary and inconsistent.

5.6 Diabetic Neuropathy

More recently, gamma-linolenic acid (GLA) derived from evening primrose oil was found noninferior to alpha-lipoic acid for reducing pain in patients with diabetic neuropathy. Earlier studies were less consistent. Early studies in diabetic neuropathy were equivocal. This area requires additional well-powered, controlled trials before conclusions can be drawn.

5.7 Multiple Sclerosis

In multiple sclerosis patients, evening primrose oil may improve fatigue and quality of life, and along with hemp seed and a diet high in antioxidants, it may improve clinical and immunological parameters. Some results were reported from multiple sclerosis after EPO consumption. However, this evidence is preliminary and based on small trials.

5.8 Other Investigated Conditions

EPO did not demonstrate effectiveness in chronic hand dermatitis, tardive dyskinesia, psoriatic arthritis, cystic fibrosis, hepatitis B, premenstrual syndrome, contact lens-associated dry eyes, acne vulgaris, breast cyst, pre-eclampsia, psoriasis, or primary Sjögren's syndrome based on available clinical trial data. Preliminary data suggest benefit in some lipid profiles, ulcerative colitis, or ocular surface diseases such as dry eye, but these findings remain early.

Several small studies have looked into whether taking evening primrose oil, fish oil, and calcium together could help slow down bone loss. The results have been mixed.

The NCCIH concludes there is not enough evidence to support the use of evening primrose oil for any health condition.

6. Dosage Forms and Study-Reported Dosages

EPO is commercially available as oral softgel capsules, hard capsules, bulk liquid oil, tinctures, and in topical preparations (creams, serums, and lotions). Evening primrose oil is generally obtained by mechanical pressing, followed by extraction with hexane; cold-pressing without solvents is also widely employed in premium preparations.

The following dosages have been reported specifically in published clinical studies:

• An open study with 21 atopic dermatitis patients administered EPO 4–6 g daily for 12 weeks.
• In a dose-dependent study in children and adolescents with atopic dermatitis, EASI scores decreased after eight weeks of EPO administration in both 160 mg and 320 mg GLA groups.
• In a randomized double-blind Korean trial with 50 mild AD patients, the first group received capsules containing 450 mg of EPO (40 mg of GLA) per capsule, while placebo capsules identical in appearance containing 450 mg of soybean oil were given to the other group, for a period of four months.
• EPO prescribed as 500 mg daily for 6 weeks has been evaluated for menopausal hot flashes.
• In one PMS trial, evening primrose oil was administered for three months, producing significant reductions in PMS severity scores.
• A 6-month clinical trial used oral EPO capsules for 38 patients with PMS.

Clinical studies on EPO in women's health confirmed its efficacy profile, but the immediate response should not be expected from it; therefore, it should be regularly used for up to 4 or 6 months.

7. Safety Considerations and Drug Interactions

General Safety Profile

Evening primrose oil is probably safe for most adults when taken orally. Less is known about its safety for children. Evening primrose oil is generally well tolerated. The most common side effects are gastrointestinal symptoms such as abdominal pain, nausea, or diarrhea. Some patients complain of bloating and gastrointestinal problems after administration of evening primrose oil. Nausea, headache, and diarrhea are the occasional effects related to evening primrose oil.

Bleeding Risk and Anticoagulant Interactions

Anticoagulants and anti-platelet drugs, herbs, and supplements reduce blood clotting. Combining oral use of evening primrose oil with them might increase the risk of bleeding. Animal research suggests that EPO has important anticoagulant and antiplatelet activity, which may last 60 days.

Seizure Risk

Phenothiazines — drugs used to treat serious mental and emotional disorders — may interact with EPO and increase the risk of seizures in some people. The Mayo Clinic advises not to take evening primrose if you have epilepsy or schizophrenia, as the supplement might raise the risk of seizures. However, this picture is complicated: research has noted that "EPO-derived omega-6 fatty acid arachidonic acid inhibits sodium ion currents and synaptic transmission, while the EPO-derived eicosanoid prostaglandin E(1) appears to have anticonvulsant activity," suggesting that some formularies should reconsider listing seizures or epilepsy as an absolute contraindication to EPO.

CYP3A4 and HIV Drug Interactions

Evening primrose should be used with care in those taking cytochrome P450 3A4 (CYP3A4) substrates — drugs affected by these enzymes — such as the cholesterol-lowering lovastatin (Altoprev). The combined HIV medication lopinavir-ritonavir (Kaletra) may be affected: evening primrose oil might slow down how quickly this medication is broken down in the body.

Prolonged Use

There has been one case report of lipoid pneumonia secondary to long-term use of EPO in a person with gastroesophageal reflux disease (GERD). Another case report warns that if EPO is taken for a prolonged period of time (more than one year), there is a potential risk of inflammation, thrombosis, and immunosuppression due to slow accumulation of EPO in the tissues.

Pregnancy and Hormonal Concerns

Evening primrose oil might raise the risk of pregnancy complications. Some types of evening primrose may act like estrogen; as a result, people with hormone-sensitive cancers should not take it. Evening primrose oil may be safe for use during pregnancy and while breastfeeding, but the evidence is not conclusive.

Evidence Characterization Summary

There is insufficient evidence to make a reliable assessment of EPO's effectiveness for most clinical indications. The strongest negative findings come from the Cochrane systematic review on atopic dermatitis, which included 27 studies and 1,596 participants and concluded no benefit. For menopausal hot flashes, a meta-analysis of six RCTs suggests modest benefit in reducing hot flash frequency. For mastalgia, PMS, and rheumatoid arthritis, evidence is either negative or inconclusive from systematic reviews. Evidence on diabetic neuropathy and multiple sclerosis remains very preliminary. In all areas, study quality is noted to be variable, with methodologic limitations frequently identified.

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