Evening Primrose Oil

Oenothera biennis L.

[Fam. Onagraceae]

Overview

Evening primrose is a plant native to North America. Traditionally, it was used externally to treat skin diseases and internally to treat breathing problems and arthritis (Manku et al., 1982; Moerman, 1998; Willard, 1992). It was one of the first medicinal plants brought back to Europe by settlers in the 16th century (Willard, 1992). Evening primrose oil (EPO) has been the subject of hundreds of scientific studies, which led to it becoming one of the most widely used botanical medicines today (Brown, 1996). EPO is sold in over 30 countries as a dietary supplement, drug, or food (Chen, 1999). In 2000, evening primrose oil ranked 10th of all herbal dietary supplements in U.S. food, drug, and, mass-market retail outlets (Blumenthal, 2001). Clinical studies have focused on its use in treating problems associated with essential fatty acid (EFA) deficiency including atopic eczema, premenstrual syndrome, inflammation, and diabetic peripheral neuropathy. EPO is relatively high in essential fatty acids (EFAs), particularly gamma-linolenic acid (GLA, 7–10%) (Leung and Foster, 1996).

Description

Evening primrose oil preparations consist of a clear, golden yellow, fixed oil extracted by cold expression, or solvent extraction, from the seeds of Oenothera biennis L. [Fam. Onagraceae] (Budavari et al., 1996; Reynolds et al., 1989), which first occur during the second year of plant growth. Evening primrose is a biennial herb, infertile for the first year (Schulz et al., 1998).

Primary Uses

Dermatology

Atopic dermatitis (Berth-Jones and Graham-Brown, 1993; Gehring et al., 1999; Hederos and Berg, 1996; Schäfer and Kragballe, 1991)

Gynecology

Mastalgia, cyclical (Wetzig, 1994; Gateley et al., 1992; Cheung, 1999)

Lactation (Cant et al., 1991)

Other Potential Uses

Diabetic neuropathy (Keen et al., 1993; Jamal and Carmichael, 1990)

PMS symptoms (Khoo et al., 1990; Ockerman et al., 1986)

Rheumathoid arthritis (Brzeski et al., 1991)

Nutritional deficiencies (essential fatty acids) (Brown, 1996)

Dermatitis: seborrhoeic dermatitis (milk crust), and atopic dermatitis in infants (Schilcher, 1997)

Infant formula fortification (Gibson and Rassias, 1990)

Dry eyes associated with Sjögren’s syndrome (Manthorpe et al., 1990)

Raynaud’s disease (Brown, 1996; Chen, 1999)

Uremic skin symptoms (Yoshimoto-Furuie et al., 1999)

Dosage

Internal

Atopic dermatitis: 4–6 capsules (500 mg) twice daily (40 mg GLA per capsule) (Hederos and Berg, 1996; Schäfer and Kragballe, 1991; Schulz et al., 1998).

Cyclical mastalgia: 6 capsules (500 mg) daily (40 mg GLA per capsule) for 4 –6 months (Cheung, 1999; Gateley et al., 1992b; McFayden et al., 1992).

Diabetic neuropathy: 8–12 capsules (500 mg) daily (Bratman and Kroll, 1999).

Lactation aid: 500 mg capsules, twice daily, morning and evening (Cant et al., 1991).

Rheumatoid arthritis: 10–20 capsules (500 mg) daily (Bratman and Kroll, 1999).

Uremic skin symptoms: 2 capsules (500 mg) twice daily (45 mg GLA per capsule) (Yoshimoto-Furuie et al., 1999).

Note: Evening primrose oil may be swallowed directly or may be taken with milk, another liquid, or with food (Newall et al., 1996). Evening primrose oil taken with food may minimize any potential gastrointestinal side effects. Concurrent ingestion of the antioxidant vitamin E will protect essential fatty acids (EFAs) from free radical damage and also prevent creation of counterproductive substances (Reddy et al., 1994). Concurrent ingestion of a daily multiple vitamin may also provide nutritional cofactors (e.g., zinc, B6, and magnesium) required for EFA metabolism (Brown, 1996).

External

Atopic dermatitis: Water-in-oil emulsion containing 20% evening primrose oil, twice daily is applied topically to affected area for at least four weeks (Gehring et al., 1999).

Duration of Administration

Internal

Evening primrose oil is a long-term therapy, and immediate results should not be expected. A patient may need evening primrose oil regularly for up to four months before a clinical response is observed (Gateley et al., 1992b; Newall et al., 1996). Evening primrose oil appears to be safe for long-term use, at least up to one year (Keen et al., 1993).

Chemistry

Evening primrose seed contains ca. 14% fixed oil (EPO), which is composed of ca. 65–75% linoleic acid (LA), 7–10% gamma-linolenic acid (GLA), plus oleic, palmitic, and stearic acids and steroids campesterol and b-sitosterol (Leung and Foster, 1996; Newall et al., 1996).

Pharmacological Actions

Human

Improves EFA composition of plasma, erythrocyte, and platelet lipids, and a-tocopherol levels in non-diabetic persons and Type 1 diabetic patients (van Doormaal et al., 1988); increases total fat and EFA content of mother’s milk (Cant et al., 1991); affects fatty acid composition of serum lipids and adipose tissue in men with low dihomogammalinolenic acid (DGLA) levels (Abraham et al., 1990); helps maintain normal cellular structures and is a precursor of prostaglandins (Chen, 1999). GLA functions as the precursor of DGLA, which is the parent of the 1-series prostanoids, and as a precursor of arachidonic acid, the parent of the 2-series prostanoids (Pizzorno and Murray, 1999).

Animal

Reduces chronic inflammation (Kunkel et al., 1981); inhibits mammary tumor growth (Karmali and Marsh, 1985); has a beneficial effect on plasma lipids and protects against diabetic nephropathy (Barcelli et al., 1990); anti-asthmatic at high doses (Dorsch and Schmidt, 1995); prevents reduced nerve conduction velocity in streptozotocin-induced diabetes mellitus in rats (Dines et al., 1995); inhibits thromboxane A2 in diabetes (Dines et al., 1996); antisecretory, anti-ulcerogenic, and cytoprotective in rats that exhibited gastric mucosal damage induced by varicose ulcerogenesis (al-Shabanah, 1997); inhibits binding of benzo(a)-pyrene to cancerous skin cell DNA in mice exposed to a two-stage carcinogenesis model (Ramesh and Das, 1998); inhibits tumor growth in mice with transplanted mammary gland adenocarcinoma (Munoz et al., 1999); alters fatty acid composition of immune system cells; immunomodulatory (Peterson et al., 1999).

In vitro

Cytostatic activity on malignant cell lines (Botha and Robinson, 1986; Leary et al., 1982); suppresses cancer cell proliferation of human osteogenic sarcoma cells (Booyens et al., 1984).

Mechanism of Action

EFAs are required for the normal structure of all cell membranes in the human body. They are not synthesized endogenously and thus must be obtained from dietary sources (Brown, 1996; Chen, 1999). Major EFAs are linolenic acid (LA) and alpha-linolenic acid (ALA). Their metabolic products [long-chain polyunsaturated fatty acids including GLA, dihomogammalinolenic acid (DGLA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA)] are functionally essential and involved in prostaglandin biosynthetic pathways (Newall et al, 1996). LA is desaturated to GLA by the enzyme delta-6-desaturase (D6D). This conversion of LA to GLA by D6D is the rate-limiting step in the metabolic pathway for EFAs. Its activity is reduced/inhibited by increased demand caused by stress, aging, alcohol, smoking, diabetes, hypertension, and inflammatory diseases including arthritis, psoriasis, and others. In these circumstances, LA accumulates in the body, and an excess of LA may further limit the activity of the D6D enzyme (Giron et al., 1989; Diboune, 1992). GLA is elongated to DGLA by the enzyme elongase and acts as a substrate for production of prostaglandins of series 1. It may also be desaturated to arachidoninc acid.

Actions of Evening Primrose Oil (EPO)

Supplies GLA: The bioactivity of evening primrose oil is due primarily to its GLA content. By supplying GLA, it bypasses the rate-limiting step in the metabolism of LA. After ingestion of evening primrose oil, GLA is rapidly absorbed and then converts directly to DGLA and other prostaglandin precursors (Chen, 1999; Pizzorno and Murray, 1999).

Acts on the prostanoid pathway (Croft et al., 1984).

Actions of Essential Fatty Acids (EFA)

Elevate levels of DGLA in plasma, neutrophils, and epidermal phospholipids. DGLA is the precursor of the anti-inflammatory substances 15-hydroxy-eicosatrienoic acid and prostaglandin E1 (Shafer and Kragballe, 1991).

May reduce rheumatoid inflammation by metabolizing to the anti-inflammatory one-series prostaglandins and competitively inhibiting the synthesis of pro-inflammatory two-series prostaglandins and four-series leukotrienes (Joe and Hart, 1993).

May inhibit papilloma formation in vivo by inhibiting the binding of benzo-(a)-pyrene to skin cell DNA and increasing the lipid peroxidation process (Ramesh and Das, 1998).

Absorbed transdermally as well as internally (Houtsmuller and van der Berk, 1981).

Contraindications

Previously not recommended for patients diagnosed with schizophrenia and/or those already receiving epileptogenic drugs such as phenothiazines, according to a data sheet produced by the leading marketer of evening primrose oil (Anon., 1994–95). However, a recently published analysis of clinical trials involving polyunsaturated fatty acids in the treatment of schizophrenia did not indicate a clear therapeutic or adverse effect of evening primrose oil supplements on schizophrenic patients (Joy, 2000).

Pregnancy and Lactation: No known restrictions (Brown, 1996; McGuffin et al., 1997). Non-teratogenic, based on animal studies (Anon., 1994–95; Horrobin, 1992). LA, GLA, and DGLA are important components of human breast milk, so it is reasonable to assume that evening primrose oil may be taken while nursing (Brown, 1996; Carter, 1988; Gibson and Rassias, 1990; Newall et al., 1996). According to the World Health Organization, pregnant or lactating women should get 5% of their total daily caloric intake from EFAs (Chen, 1999).

Adverse Effects

Adverse effects are rare at recommended dosages and are reported by less than 2% of people using evening primrose oil long-term (Brown, 1996; Chen, 1999). Occasional adverse effects include headache (Barber, 1988; Gateley et al., 1992b; Hänsel et al., 1993), mild nausea (Barber, 1988; Cheung, 1999; Gateley et al., 1992b; Hänsel et al., 1993), and abdominal bloating (Gateley et al., 1992b). Overdose symptoms include loose stools and abdominal pain (Newall et al., 1996).

Drug Interactions

Early reports suggested that GLA might exacerbate temporal lobe epilepsy in schizophrenic patients being treated with epileptogenic drugs such as phenothiazines (Anon., 1994–95), though this possible effect has not been confirmed (Bratman and Kroll, 1999). Other reports have suggested that steroids and nonsteroidal anti-inflammatory drugs may interfere with GLA metabolism (Brenner, 1981), though this theoretical concern has not been proven (Brown, 1996). Steroids have been reported to inhibit the D6D enzyme, whereby the metabolism of LA to GLA is inhibited. For patients taking steroidal drugs, supplementation with a source of GLA such as evening primrose oil, borage oil (Borago officinalis), or black current oil (Ribes nigrum) may be beneficial (Marra and de Alaniz, 1990). In one clinical trial, 38 estrogen-dependent breast cancer patients showed a faster clinical response to tamoxifen after oral ingestion of GLA (as found in EPO) (Brinker, 2001).

American Herbal Products Association (AHPA) Safety Rating

Class 1: Herbs that can be safely consumed when used appropriately (McGuffin et al., 1997).

Regulatory Status

Canada: OTC schedule oral drug, requiring pre-market authorization and assignment of Drug Identification Number (DIN) (Health Canada, 2001).

France: Used in cosmetic products and toiletries (Bruneton, 1999).

Germany: Capsules containing 0.5 g evening primrose oil (corresponding to 40 mg GLA) are approved drugs for treatment and symptomatic relief of atopic eczema (Schulz et al., 1998).

Italy: No information available.

Sweden: Natural remedy for self-medication requiring marketing authorization by the Medical Products Agency (MPA) (Tunón, 1999; WHO, 1998). The only evening primrose-containing product listed in the “Authorised Natural Remedies” (Epogam^®) was removed to the Deregistered Natural Remedies list in April of 2000 (MPA, 2001).

Switzerland: Herbal medicine with positive classification (List D) by the Interkantonale Konstrollstelle für Heilmittel (IKS) and corresponding sales category D with sale limited to pharmacies and drugstores, without prescription (Morant and Ruppanner, 2001; Codex, 2000).

U.K.: Approved by the Department of Medicine for treatment of atopic eczema and mastalgia (Chen, 1999).

U.S.: Dietary supplement (USC, 1994).

Clinical Review

Twenty-two studies are outlined in the following table “Clinical Studies on Evening Primrose,” with a total of 1,154 participants. All but six of these studies (Whitaker et al., 1996; Oliwiecki and Burton, 1994; Berth-Jones and Graham-Brown, 1993; Oliwiecki et al., 1993; Dove et al., 1999; Jenkins et al., 1996) demonstrated positive effects for indications including PMS, dermatological conditions, diabetic neuropathy, and arthritis. The table includes seven double-blind, placebo-controlled (DB, PC) studies investigating the use of evening primrose oil in dermatological conditions including uremic skin symptoms (Yoshimoto-Furuie et al., 1999), chronic hand dermatitis (Whitaker et al., 1996), atopic dermatitis (Berth-Jones and Graham-Brown, 1993; Gehring et al., 1999; Hederos and Berg, 1996), chronic stable-plaque psoriasis (Oliwiecki and Burton, 1994), and psoriatic arthritis (PsA) (Veale et al., 1994). Treatment of PMS symptoms was the subject of two DB, PC studies (Khoo et al., 1990; Ockerman et al., 1986). Other subjects of DB, PC studies in the table included treatment of cyclic mastalgia (Cheung, 1999), diabetic neuropathy (Keen et al., 1993; Jamal and Carmichael, 1990), rheumatoid arthritis (Brzeski et al., 1991), menopausal hot flash (Chenoy et al., 1994), effect on fat composition and content of human milk (Cant et al., 1991), and the effect of survival time of patients with primary liver cancer (van der Merwe et al., 1990). A recent study on pregnant, low-risk, nulliparous women measured pregnancy length and activephase labor outcomes (Dove et al., 1999). A meta-analysis of nine PC studies on atopic eczema correlated clinical improvement with a rise in plasma essential fatty acids (Morse et al., 1989). Improvement in reported itching symptoms was highly significant (p<0.01) compared to placebo. EPO showed a progressive effect as well as a dose/response relationship in the 311 atopic eczema patients evaluated in the nine trials. The protocol has been established for a systematic review of studies on EPO for the treatment of premenstrual syndrome (PMS), but it has not yet been concluded (Strid et al., 2001).

Branded Products

Efamast^®500 mg evening primrose oil: Scotia Pharmaceuticals Ltd. / Scotia House / Sterling / Scotland / FK9 4TZ / U.K. / http://fox.nstn.ca/~scotlib/index.html. 1 capsule contains 40 mg of GLA.

Efamol^®500 mg evening primrose oil: Scotia Pharmaceuticals Ltd. 75.0% linoleic acid (LA), 9.0% gamma-linolenic acid (GLA), 8.5% oleic acid (OE).

Efamol^® Marine 500 mg: Scotia Pharmaceuticals Ltd. 430 mg evening primrose oil and 107 mg marine fish oil, providing
40 mg GLA, 20 mg EFA, 11 mg DHA, vitamin E.

Epogam^® 500 mg EPO: Scotia Pharmaceuticals Ltd. 50 mg of GLA and 10 mg vitamin E per capsule.

Quest Vitamins: Quest Vitamins / 7080 River Road #129 / Richmond, BC / V6X 1X5 / Canada / Tel: (604) 273-0611 / Email: thartz@van.boehringer-ingelheim.com / www.questvitamins.com. Capsule containing 500 mg evening primrose oil.

Scotia Cream: Scotia Pharmaceuticals Ltd. Cream containing 0.1% beta-methasone valerate and 10% evening primrose oil.

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