Herb-Drug Interactions: Evening primrose oil

2011

Oenothera biennis L. (Onagraceae)

Synonym(s) and related species

Common evening primrose, King’s cureall, Sun drop, Tree primrose.

Oenothera lamarkiana, Onagra biennis (L.) Scop.

Pharmacopoeias

Evening primrose oil (British Ph 2009, European Ph, 6th ed., 2008 and Supplements 6.1, 6.2, 6.3 and 6.4).

Constituents

The oil from evening primrose seeds contains the essential fatty acids of the omega-6 series, linoleic acid (about 65 to 85%) and gamolenic acid (gamma-linolenic acid, about 7 to 14%). Other fatty acids include oleic acid, alpha-linolenic acid, palmitic acid and stearic acid.

Use and indications

Evening primrose oil is used as a food supplement to provide essential fatty acids. It is also used for atopic eczema and mastalgia; however, in the UK licences for two prescription products containing gamolenic acid derived from evening primrose oil were withdrawn in 2002, due to lack of evidence in support of efficacy.

Other conditions for which it is used include rheumatoid arthritis, premenstrual syndrome, menopausal symptoms, chronic fatigue syndrome and attention deficit hyperactivity disorder. Evening primrose oil has also been used topically as a cream, for the relief of dry or inflamed skin. Traditionally it has been used for asthma, whooping cough, gastrointestinal disorders, and as a sedative painkiller. In manufacturing, evening primrose oil is used in soaps and cosmetics. The root of evening primrose has been used as a vegetable.

Pharmacokinetics

In in vitro experiments, cis-linoleic acid, was found to be a modest inhibitor of the cytochrome P450 isoenzyme CYP2C9 (but this is not expected to result in clinically relevant effects on drug metabolism, see warfarin and related drugs), and a modest to minor inhibitor of, in order of potency, CYP1A2, CYP2C19, CYP3A4 and CYP2D6.

Interactions overview

Evening primrose oil has been predicted to interact with antiplatelet and anticoagulant drugs, but data supporting this prediction are limited. Although seizures have occurred in a few schizophrenics taking phenothiazines and evening primrose oil, no adverse effects were seen in others, and there appears to be no firm evidence that evening primrose oil should be avoided by epileptic patients.

Evening primrose oil + Antiplatelet drugs

Evening primrose oil can inhibit platelet aggregation and increase bleeding time. It has therefore been suggested that it may have additive effects with other antiplatelet drugs, but evidence of this is generally lacking.

Clinical evidence

In 12 patients with hyperlipidaemia given evening primrose oil 3 g daily for 4 months, platelet aggregation decreased and bleeding time increased by 40%. The evening primrose oil was given in the form of six 500-mg soft-gel capsules and the daily dose contained linoleic acid 2.2 g and gamolenic acid 240 mg.

Experimental evidence

Similar findings to the clinical study above have been reported in animals given evening primrose oil or gamolenic acid.

Mechanism

Prostaglandin E1 (which has antiplatelet properties) and thromboxane (which promotes platelet aggregation) are formed from gamolenic acid. Supplementing the diet with gamolenic acid has been shown to augment the production of prostaglandin E1 and, because prostaglandin E1 is also preferentially formed (the conversion of gamolenic acid to thromboxane is slower), evening primrose oil could inhibit platelet aggregation. This effect could be additive with the effects of other antiplatelet drugs.

Importance and management

Information is limited to one clinical study, in which patients were not taking conventional antiplatelet drugs, and experimental data. Based on the potential antiplatelet effects of evening primrose oil, some authors suggest that patients taking antiplatelet drugs should use evening primrose oil cautiously or not at all. This seems overly cautious because evening primrose oil is a widely used herbal product, and was formerly used as a prescription product in the UK, and clinical reports of an interaction have yet to come to light. Furthermore, the concurrent use of two conventional antiplatelet drugs is not uncommon.

Evening primrose oil + Food

No interactions found.

Evening primrose oil + Herbal medicines

No interactions found.

Evening primrose oil + NSAIDs

The interaction between evening primrose oil and NSAIDs is based on a prediction only.

Evidence, mechanism, importance and management

Gamolenic acid, a major constituent of evening primrose oil, is a precursor of prostaglandin E1; which inhibits the synthesis of tumour necrosis factor-a (which has an important effect in the inflammatory processes of rheumatoid arthritis). Supplementing the diet with gamolenic acid has been shown to augment the production of prostaglandin E1; which has a rate-limiting step mediated by cyclooxygenase-2. Theoretically, the production of prostaglandin E1, and therefore the anti-inflammatory effects of gamolenic acid, could be opposed by the concurrent use of NSAIDs because both selective and non-selective NSAIDs inhibit cyclooxygenase-2. However, evening primrose oil is often used alongside conventional treatments for arthritis and two clinical studies found that high doses of gamolenic acid reduced pain and swelling of the joints of arthritic patients when given with usual doses of NSAIDs. This theoretical interaction therefore appears to be of little clinical importance.

Evening primrose oil + Phenothiazines

Although seizures have occurred in a few schizophrenics taking phenothiazines and evening primrose oil, no adverse effects were seen in others, and there appears to be no firm evidence that evening primrose oil should be avoided by epileptic patients.

Clinical evidence

Twenty-three patients were enrolled in a placebo-controlled study of evening primrose oil in schizophrenia. During the treatment phase, patients were given 8 capsules of Efamol in addition to their normal medication. Seizures developed in 3 patients, one during treatment with placebo. The other two patients were taking evening primrose oil: one was receiving fluphenazine decanoate 50 mg once every 2 weeks and the other fluphenazine decanoate 25 mg once every 2 weeks with thioridazine, which was later changed to chlorpromazine. In another study, 3 long-stay hospitalised schizophrenics were taking evening primrose oil. Their schizophrenia became much worse and all 3 patients showed EEG evidence of temporal lobe epilepsy.

In contrast, no seizures or epileptiform events were reported in a crossover study in 48 patients (most of them schizophrenics) taking phenothiazines when they were given evening primrose oil for 4 months. Concurrent use was also apparently uneventful in another study in schizophrenic patients.

Experimental evidence

No relevant data found.

Mechanism

Not understood. One suggestion is that evening primrose oil possibly increases the well-recognised epileptogenic effects of the phenothiazines, rather than having an epileptogenic action of its own. Another idea is that it might unmask temporal lobe epilepsy.

Importance and management

The interaction between phenothiazines and evening primrose oil is not well established, nor is its incidence known, but clearly some caution is appropriate during concurrent use, because seizures may develop in a few individuals. There seems to be no way of identifying the patients at particular risk. The extent to which the underlying disease condition might affect what happens is also unclear.

No interaction between antiepileptics and evening primrose oil has been established and the reports cited above. appear to be the sole basis for the suggestion that evening primrose oil should be avoided by epileptics. No seizures appear to have been reported in patients taking evening primrose oil in the absence of phenothiazines. One review, analysing these two reports, goes as far as suggesting that formularies should now remove seizures or epilepsy as an adverse effect of evening primrose oil because the evidence for the seizures clearly point to the phenothiazines taken. Moreover, the manufacturers of Epogam, an evening primrose oil preparation, claim that it is known to have improved the control of epilepsy in patients previously uncontrolled with conventional antiepileptic drugs, and other patients are said to have had no problems during concurrent treatment.

Evening primrose oil + Warfarin and related drugs

The information regarding the use of evening primrose oil with warfarin is based on experimental evidence only.

Clinical evidence

No interactions found.

Experimental evidence

In vitro, cis-linoleic acid was found to be a moderate inhibitor of the cytochrome P450 isoenzyme CYP2C9, which is the main isoenzyme involved in the metabolism of warfarin. However, it was 26-fold less potent than sulfaphenazole, a drug known to have clinically relevant inhibitory effects on CYP2C9 in vivo.

Mechanism

Prostaglandin E1 (which has antiplatelet properties) and thromboxane (which promotes platelet aggregation) are formed from gamolenic acid. Supplementing the diet with gamolenic acid has been shown to augment the production of prostaglandin E1 and, because prostaglandin E1 is also preferentially formed (the conversion of gamolenic acid to thromboxane is slower), evening primrose oil could inhibit platelet aggregation. This effect could slightly increase the risk of bleeding with anticoagulants.

Importance and management

Evening primrose oil seems unlikely to alter the pharmacokinetics of warfarin. Other coumarins are metabolised by a similar route to warfarin, and are therefore also unlikely to be affected. However, based on the potential antiplatelet effects of evening primrose oil, some authors suggest that patients taking anticoagulants should use evening primrose oil cautiously or not at all. This seems overly cautious because evening primrose oil is a widely used herbal product, and was formerly used as a prescription product in the UK, and clinical reports of an interaction have yet to come to light.