Table 2.

Characteristics of included clinical trial studies in the systematic review of EPO effectiveness (orally administered) on inflammatory diseases

No.	Author	Type and duration of disease	Number of participants			Female/Male ratio			Age		Type of intervention and dosage
			Intervention	Control		Intervention	Control		Intervention	Control	Intervention	Control
1	Tomic-Smiljanic [17]	RA 59 months, SD ± 60 (12–180 months	20	20 in fish oil 20 placebo (only previous described rheumatologic therapy in the period of 3 months)		20/0	30/0		57,3 ± 8: group 2	Group 1: 54 ± 8 Group 3: 59 ± 7.5	daily after meals 2 gel capsules Omega-3 Cardio® and 2 gel capsules EPO each cap = 1300mg EPO (LOQ = 2600 mg/day)	daily after meals 5000 mg of omega-3 PUFA (5 gel capsules Omega-3 Cardio®/
2	BELCH [18]	RA 5 YEARS	31 (16 patients: EPO, 15: EPO/fish oil)	18		EPO: 15/1 EPO/FO: 11/4	17/1		EPO: 46 (35–68) EPO/FO: 53 (28–73)	48 (30–74)	3 cap 4 times a day (540 mg GLA/ 450 mg GLA + 240 mg EPA) (LOQ = 2600 mg/day)	3 cap 4 times a day (liquid paraffin)
3	BRZESKI [19]	RA 8 YEARS	19	21		17/2	15/6		60 (54–77)	61 (51–67)	6g/day (EPO) (LOQ = 6000 mg/day)	6g/day (olive oil)
4	JANTTI [20]	RA / The duration of RA was 13 years in the EPO group and 10 years in the olive oil group	10	10		9/1	9/1		50	38	10 ml twice daily (EPO) (LOQ = 20 ml/day)	10 ml twice daily (olive oil)
5	Veselinovic [21]	RA/59 ± 60 month (12–180 months)	40 (20:FO/ 20: EPO + OMEGA)	20		40/0 (Group 1 = group 2 = 20 patients)	20/0		Group1: 54 ± 8/ group 2: 57 ± 8	59 ± 7	5g fish oil (5g)/ 2 omega cap + 2 EPO (2600mg) cap after meal (LOQ = 2600 mg/day)	described rheumatologic therapy
6	Jamal [22]	Diabetic Peripheral/ minimum duration of symptoms of neuropathy was 6 months and of diabetes 3 years	12	10		7/5	5/5		53 ± 19 (21–74)	55 ± 15 (23–74)	4 cap twice daily (8 cap:4g) (LOQ = 4000 mg/day)	4 cap twice daily (8 cap:4g)
7	Arisaka [23]	Diabetes Mellitus//5–5.3 years	6 (EPO)	5 (indistinguishable placebo capsule)		6/5			12 years	13 years	2 capsules (each cap = 360 mg of LA and 45 mg of GLA) daily for 4 months then 4 capsules daily for a further 4 months (LOQ = 1000 mg/day)	2 daily for 4 months then 4 capsules daily for a further 4 months
8	Bamford [24]	AE	123						49children (ages 2 to 16 years; mean, 9.1) and 74 adults (ages 16 to 66 years; mean, 37.7)		Children (subjects 15 years old or younger) received two or four capsules twice daily, and adults received six or eight capsules twice daily Each cap = 500 mg EPO (LOQ = 1000 mg/day)	Children (subjects 15 years old or younger) received two or four capsules twice daily, and adults received six or eight capsules twice daily Each cap = 500 mg Liquid paraffin
9	MANKU [25]	AE/ history beginning in childhood, together with a personal and/or family history of other atopic disorders	41 (A → 16 patients, B → 13, C → 12)	50			18/32		mean age 24 years		2, 4, and 6 g/day (A,B,C) EPO (LOQ = 2000 mg/day)
10	SCHALIN-KARRILA	AE	14	11		16/9			19 to 31 years		Four capsules twice daily (EPO) Each cap = 360 mg linoteic acid, 50 mg oleic acid and 45 mg GLA (LOQ = 4000 mg/day)	Four capsules twice daily Each cap = 500 mg of liquid paraffin
11	WRIGHT [26]	AE (every patient also had either a family history of atopy or a personal history of other atopic symptoms. In every patient the disease was moderate or severe)	81	18					60 adults aged 15–58 years and 39 children aged 8 months to 14 years		Group A: two capsules twice daily, group B: four capsules twice daily, group C: six capsules twice daily. In the children’s group, 20 received one capsule twice daily (group D) Each cap = 360 mg of LA and 45 mg of GLA (LOQ = 500 mg/day)	two capsules twice daily (group E) each cap = liquid paraffin: 500mg
12	Breth-jones [27]	Atopic dermatitis	133 were enrolled								6 cap twice/day (500 mg EPO/ 430 mg EPO + 107 mg fish oil (LOQ = 6000 mg/day)	6 cap twice/day (liquid paraffin: adults olive oil: children)
13	Whitaker [28])	Chronic Hand Dermatitis /More than 1 year	20	19					19–75 years		12 cap/day (each cap = 500 mg Epogam) (LOQ = 6000 mg/day)	12 cap/ day (each cap = 500 mg sunflower oil)
14	EBDEN [29]	Atopic Asthma	12			8/4			mean age: 33 years (range 20–52)		two Efamol capsules four times daily (360 mg of LA and 45 mg GLA) (LOQ = 4000 mg/day)	two capsules four times daily (500 mg of liquid paraffin)
15	Hederos [30]	atopic dermatitis (epogam:0.9 years/placebo: 1.6 years) and asthma	eczema			eczema			eczema		1–12 years: 4 capsules twice daily/ over 12 years: 6 capsules twice daily → each cap = 500 mg EPO: 40 mg GLA + 10 mg vit E (LOQ = 4000 mg/day)	1–12 years: 4 capsules twice daily/ over 12 years: 6 capsules twice daily → Each cap = 500 mg sunflower oil + 10 mg vit E
			30	30		17/13	17/13		7.5 (1–14)	8.6 (2–16)
			asthma			asthma			asthma
			12	10		5/7	4/6		9.3 (4–14)	10.9 (3–16)
16	Blommers [31]	severe chronic mastalgia/ cyclic or noncyclic mastalgia for > 6 months, (2) an average of ≥ 7 and a minimum of 5 days with breast pain per menstrual cycle	90 (each group 30)	30		90/0	30/0		36.8 ± 6.2	22	3g/day (Group FC: fish oil and control oil, group EC: EPO and control oil, group EF: fish oil + EPO) (LOQ = 3000 mg/day)	(group CC: two control oils)
17	Goyal [32]	Mastalgia average length 23–33 days), moderate to severe mastalgia of a minimum of 3-months duration requiring drug treatment, with at least 7 days of pain per menstrual cycle	417	138		280/0	275/0		GLA + multivitamines: 39.6 (6.8) GLA + multivitamines: 39.7 (6.0)	Placebo + multivitamines: 39.2 (6.5) Both placebo: 39.0 (6.6)	1 Cap/day (a:500 mg EPO (40 mg GLA) and 10 mg vit E. b: 500 mg coconut oil + 10 mg vit E. c:3 mg beta carotene, 100 mg vitamin C, 25 mg vitamin B6, 10 mg zinc, 10 mg niacin and 455 µg selenium d: 255 mg fractionated coconut oil → ((a) GLA and antioxidant/(c) GLA and placebo antioxidants (LOQ = 500 mg/day)	(b) placebo fatty acids and antioxidants/(d) placebo fatty acids and placebo antioxidants
18	Pye [33]	Mastalgia/ for at least 6 months, for a minimum of 10 days in each cycle				/0	/0				6 cap/day
19	Qureshi [34]	Mastalgia/moderate to severe breast pain of two to three months duration over a period of one year	25	25		25/0	25/0		15 to 50 years		500mg twice daily OEP capsules (Efamol) (LOQ = 1000 mg/day)	application to the affected area twice a day topical NSAID in 0.5% Piroxicam gel (Feldene
20	Nasri [35]	polycystic ovary syndrom	30	30		30/0	30/0		18–40 years		1000 IU vitamin D3 plus 1000 mg EPO (LOQ = 1000 mg/day)	placebo
21	Farzaneh [36]	menopausal hot flashes mean duration of menopause was 2.4 ± 1.8 (range: 1–7) years	56			56/0			45–59 years		two capsules per day = 1g/day (totally 90 capsules for 6 weeks) (LOQ = 1000 mg/day)	Placebo:1g/day
22	Gateley [37]	benign breast disorders /mastalgia	36			36/0					8 capsule (320 mg GLA)s daily (EPO) (LOQ = 4000 mg/day)	8 capsules liquid paraffin
23	Gateley [37]	Breast cyst	200			200/0					six capsules daily (240 mg GLA) (LOQ = 1500 mg/day)	six capsules daily placebo
24	Gupta	Hypercholesterolemia and Mixed Dyslipidemia	30	30		21/9	22/8		46.80 ± 7.43 years	45.50 ± 6.76 years	1 cap/day after 2 main meal (250 mg EPO) (LOQ = 250 mg/day)	1 cap/day after 2 main meal placebo
25	Ishikawa [38]	hypercholesterolemic	19			7/12			42–63 years		3.6g/day (four capsules containing 0.3 g of EP three times daily,) (LOQ = 3600 mg/day)	3.6g/day (four capsules containing 0.3 g of sunflower oil three times daily)
26	JENKINS [39]	chronic hepatitis B/ presence of hepatitis B surface antigen in two serum samples at least 6 months apart	10 (11 entered)	10 (13 entered)		1/9	2/8		59.4 ± 9.9	45.6 ± 13.5	4g/day (2g twice daily before meal( each cap: 500 mg + 10 mg Vit E) (LOQ = 4000 mg/day)	4 capsules (2 g) twice daily before meals liquid paraffin:
27	Khoo [40]	PMS	19	19		19/0	19/0		20–40 years
28	Kokke [41]	lens associated dry eye/ wearing monthly or daily soft contact lenses	28	24		28/0	24/0		46.4 (12.6)	37.3 (10.7)	6 cap/day (EPO)	6 cap/day Olive oil
			76 entered
29	Laivuori [42]	Pre-eclamptic	7 (EPO:4, FO:3)	5		7/0	5/0		EPO: 32.0 (23–40), FO: 30.3 (24–40)	30.2 (26–32)	10 g/day (EPO, fish oil) (LOQ = 10,000 mg/day)	Olive oil (Each cap: 500 mg of maize oil and 500 mg of olive oil)
			18 entered (primrose oil (n = 7), with fish oil (n = S), or with placebo (n = 6))
30	MOODLEY	Pre-Eclampsia /32–36 years	23	24		23/0	24/0		(17–27)	( 16–27)	8 cap/day (each cap: 500 mg EPO) (LOQ = 4000 mg/day)	8 cap/day
31	Makrides [43]	Erythrocyte fatty acid changes of term infants	13	32		9/4	26/17				(FO + EPO) one sachet to 200 mL (LOQ = 200 ml/day)	placebo powder to 210 mL
				19 PLACEBO	23 fully breast feed		11/8	14/9
32	Manthorpe [44]	Primary Sjogren's syndrome/ 1–40 YEARS: FEMALE, 2–3 YEARS: MALES	36			33/3			34–76 YEARS		three capsules of Efamol twice daily and three tablets of Efavit twice daily (LOQ = 3000 mg/day)	three tablets of placebo
33	OLIWIECKI [45]	Primary Sjogren's syndrome	37						16–70 years		12 cap/day (2 divided dose) Each cap = (430 mg EPO) (LOQ = 6000 mg/day)	12 cap/day (2 divided dose) Each cap = 500 mg Liquid paraffin
34	Theander	Primary Sjogren's syndrome/ 6–14 years (10)	87			79/8			50–68 years (62)		EPO: 800 mg or 1600 mg per day Each cap = 40 or 80 mg (2 different dose in 2 groups) (LOQ = 800 mg/day)	1600 mg per day Corn oil emulsion
35	Ka ´zmierska [46]	Acne Vulgaris	25	25					18 to 30 years (mean age 22.0 ± 2.07 years)		4 cap/day (each:510 mg/ 2 morning and 2 evening (LOQ = 2000 mg/day)	4 cap/day (each = 10 to 40 mg of isotretinoin
									22.5 ± 1.92 years	21.6 ± 2.14 years
36	Oxholm [47]	Primary Sjogren's syndrome/ 7 years (range 1–23)	28			24/4			Mean age was 51 years (range 32–71)		one period of 8 weeks with 3 g Efamol daily (6 capsules) (LOQ = 3000 mg/day)	another period of 8 weeks with identical looking placebo capsules
37	Iran/Soheila Rezapour-Firouzi a,b, ∗ , Seyed Rafie Arefhosseini	multiple sclerosis/A: 6.26 ± 3.9/ B: 7.55 ± 5.08/ C: 6.60 ± 4.0	43 (A:23, C:20)	22		12/31 (A: 7/16, C: 5/15)	11/11		A: 34.2 ± 7.5 C: 33.7 ± 7.8	35.9 ± 7.8	18—21 g/day (6—7 g, three times daily) (‘‘Group A’’ received co-supplemented hemp seed and evening primrose oils with advised Hot-nature diet (LOQ = 1800 mg/day)	‘‘Group B’’ who received olive oil, ‘‘Group C’’ who received the co-supplemented oils)
38	Rezapour-Firouzi [48]	multiple sclerosis/A: 6.26 ± 3.9/ B: 7.55 ± 5.08/ C: 6.60 ± 4.0	43 (A:23, C:20)	22		12/31 (A: 7/16, C: 5/15)	11/11		A: 34.2 ± 7.5 C: 33.7 ± 7.8	35.9 ± 7.8	18—21 g/day (6—7 g, three times daily) (‘‘Group A’’ received co-supplemented hemp seed and EPO with advised Hot-nature diet (LOQ = 1800 mg/day)	‘‘Group B’’ who received olive oil, ‘‘Group C’’ who received the co-supplemented oils)
39	Rezapour-Firouzi [49]	multiple sclerosis/A: 6.26 ± 3.9/ B: 7.55 ± 5.08/ C: 6.60 ± 4.0	43 (A:23, C:20)	22		12/31 (A: 7/16, C: 5/15)	11/11		A: 34.2 ± 7.5 C: 33.7 ± 7.8	35.9 ± 7.8	18—21 g/day (6—7 g, three times daily) (‘‘Group A’’ received co-supplemented hemp seed and EPOs with advised Hot-nature diet (LOQ = 1800 mg/day)	‘‘Group B’’ who received olive oil, ‘‘Group C’’ who received the co-supplemented oils)
40	Rezapour-Firouzi [50]	multiple sclerosis/A: 6.26 ± 3.9/ B: 7.55 ± 5.08/ C: 6.60 ± 4.0	43 (A:23, C:20)	22		12/31 (A: 7/16, C: 5/15)	11/11		A: 34.2 ± 7.5 C: 33.7 ± 7.8	35.9 ± 7.8	18—21 g/day (6—7 g, three times daily) (‘‘Group A’’ received co-supplemented hemp seed and evening primrose oils with advised Hot-nature diet (LOQ = 1800 mg/day)	‘‘Group B’’ who received olive oil, ‘‘Group C’’ who received the co-supplemented oils)
41	Vaddadi [51]	Tardive Dyskinesia	21	17		9/11	7/10		mean age of 52.7 years		12 capsules of Efamol in divided doses (LOQ = 6000 mg/day)	12 capsules of placebo in divided doses
42	VEALE [52]	Psoriatic arthritis/ 1–30 years	19	19		12/7	12/7		18–76): 40	(25–58): 40	12 capsules of Efamol daily Each cal = 480 mg GLA, 240 mg EPA and 132 mg of DHA (LOQ = 6000 mg/day)	12 capsules of placebo daily

No.	Author	Duration of intervention	Monitored inflammatory factors			Outcome	side effect
			diagnosis	Endpoint	Time point of blood samples
1	Tomic-Smiljanic [17]	3 months	CRP → group 1: 12.4 ± 8.2 Group2: 16.0 ± 18.3 group3: 12.7 ± 7.2 ESR → group1: 35 ± 24 Group2: 36.7 ± 19.2 Group3: 33.25 ± 17.14			There was no significant difference in neither ADP nor arachidonic acid-induced platelet aggregation between the groups of patients with RA who used omega-3 PUFA and the patients with RA who used omega-3 PUFA and EPO	Mild gastrointestinal distress (mild diarrhea, abdominal pain, indigestion or nausea less than 72 h)
2	BELCH [18]	15 months	ESR → EPO: 4–81 (22) EPO/FO: 4–55 (26) placebo: 3–75 (30) CRP → EPO: 10–43 (19), EPO/FO: 10–38 (13), placebo: 8–76 (19)			94% of the EPO and 93% of the EPO/fish oil group felt a subjective improvement in their condition at 12 months. Most patients on active treatment recorded an increase in their general sense of wellbeing. In this study we have shown that it was possible for some patients with RA to decrease or stop NSAID treatment when EPO or EPO/fish oil was given. despite the lack of objective improvement in symptoms on the active oils, there was a very definite subjective improvement. The mechanism of this is unclear, but two alternative explanations are possible	nausea, diarrhoea, headache
3	BRZESKI [19]	6 months	ESR → EPO: 19–59 (41) placebo: 11–69 (42) CRP → EPO:10–45 (14), placebo: 10–53 (13)			No patients stopped NSAIDs but three in each group reduced the dose of NSAID—in all patients this was by only one tablet, e.g. ibuprofen 400 mg 3 times to 2 times a day—and one patient in the EPO group increased NSAID dosage. Four patients taking placebo and one taking EPO reduced analgesia dosage, and two in each group increased dosage. EPO produced marked reduction in morning stiffness and articular index, although only the former reached statistical significance
4	JANTTI [20]	12 weeks	APO-A1 (g/l → EPO:1–366 (0.158), placebo: 0–965 (0–089) APO-A2 (g/l) → EPO: 1–445 (0–237), placebo: 0–89 (0–227)	APO-A1 (g/l → EPO: 1–330 (0–197), placebo: 1–188 (0–08) APO-A2 (g/l) → EPO: 1–149 (0–259), placebo: 0–752 (0–133)		Serum total cholesterol and triglyceride concentrations did not change in either of the groups, but the serum HDL-cholesterol concentration increased slightly during olive oil treatment. EPO had no effect on the serum concentration of apolipoprotein A-I, whereas that of apolipoprotein B decreased in all three patients studied. Apolipoprotein A-I increased in all four studied patients treated with olive oil, whereas apolipoprotein B decreased in three patients
5	Veselinovic [21]	12 weeks	ESR → group1: 35.0 ± 24.1 Group 2: 36.7 ± 19.2, group3: 33.3 ± 17.1 CRP → group1: 12.4 ± 8.2, group2: 16.0 ± 18.3, group3: 12.7 ± 7.2	ESR → group1: 23.2 ± 16.6, group2: 19.9 ± 10.8, group3: 24.1 ± 13.9, CRP → group1: 7.3 ± 2.9, group2: 7.1 ± 5.5, group3: 6.9 ± 3.5		The number of painful joints and VAS score in both supplement groups (p ≤ 0.001) decreased significantly after 12 weeks, but not in the control group, a significant decrease in DAS 28 score was observed in the second group, which is n-3 have consumed PUFA. and EPO (4.76 ± 0.85 to 3.79 ± 0.72, group II). After 12 weeks of supplementation, when all groups were compared, the levels of EPA, DHA and n-3 PUFA were higher, and the ratio of n-6 to n-3 in both supplement groups was lower than that of control patients. GLA and AA were more in group II (fish oil + EPO) than groups I and III. The inflammatory factors decreased at the end of trial	Mild gastrointestinal discomfort (mild diarrhea, abdominal pain, dyspepsia or nausea lasting less than 72h
6	Jamal [22]	6 months	HbA1 (%) → EPO: 9.1 ± 0.4, Placebo: 8.8 ± 0.3	HbA1 (%) → EPO: 8.7 t 0.3, placebo: 8.9 ± 0.4		There was no significant change in the HbA, in either the active or the placebo group at the beginning or end of the trial period. At the end of the 6 months, no significant changes occurred in the fatty acid profile in the placebo group (Table 3). However, in the active treatment group levels of arachidonic, y-linolenic, and dihomogammalinolenic acids all increased significantly (towards normal values) by the end of the trial
7	Arisaka [23]	8 months	PGE2 (pg/ml) → EPO: 63.9 ± 9.0, placebo: 59.5 ± 10.5 PGF2α (pg/ml) EPO: 189.2 ± 82.2,placebo: 173.6 ± 56.4	PGE2 (pg/ml) → EPO: 38.6 ± 7.2, placebo: 63.2 ± 11.2 PGF2α (pg/ml) EPO: 158.5 ± 42., placebo: 162.4 ± 61.5		EPO supplementation may be beneficial in diabetes by preventing various vascular complications of diabetes that may be related to altered EFA and PG metabolism. EFA studies in diabetes have shown that the levels and rates of formation of long-chain EFAs, such as DGLA, arachidonic acid, and eicosapentaenoic acid, are consistently low and levels of PGE2 and PGF2, are raised, and PGEl formation is impaired. EPO capsules significantly increased the DGLA level to the normal range. EPO also contains linoleic acid, but no significant changes in serum linoleic acid were demonstrated. Some of this extra linoleic acid would have been converted to GLA and DGLA. it is suspected that increased plasma PGEl production subsequent to increased serum DGLA (the precursor of PGEJ suppresses production of series 2 PGs, such as PGE2
8	Bamford [24]					no differences in measurements of weight, triceps, skin-fold thickness, or blood pressure (systolic and diastolic, taken while the patient was seated) or in the ratings of appetite and stress taken at each of the three visits were found. only one change during the trial (statistically significant at the p < 0.03 level) were observed, an increase in plasma arachidonic acid during treatment with evening primrose oil. The change was observed in only a small group-children taking the low child's dose (n = 6)	Nausea and bloating occurred in five subjects taking EPO and in one case taking placebo. Hyperactivity was developed in three children taking placebo and only one child taking EPO
9	MANKU [25]	24 weeks				Treatment with Efamol produced highly significant elevations in 2o:3n-6 and 2o:4n-6. DGI.A became normal, but arachidonic acid remained well below normal even after 3 months' treatment. The C-22 n-6 fatty acids were unchanged as were all the n-3 EFAs
10	SCHALIN-KARRILA	12 weeks				EPO had a statistically significant improvement in the overall severity and grade of inflammation and reduction in the surface area involved like dryness and itch. there was a significant but smaller improvement in the placebo group. EPO had no significant effect on the amount of TXB; released into the serum during blood clotting. Levels of plasma TXB; and PGE, were also not significantly altered by EPO After 6 weeks the level of 6-keto-PGF|, was significantly increased in the EPO group and decreased in the placebo group, when compared with pre-treatment levels, but after 12 weeks the levels were close to the pre-treatment values. EPO had no effects on oleic acid (18: in9), palmitic acid (16:0), 11,14,17- eicosatrienoic acid (20: 3n3)	No side-effects due to EPO were observed
11	WRIGHT [26]	12 weeks				Each final symptom score (after 12 weeks of drug or placebo) was subtracted from the initial symptom score for each patient, and these values were then compared for evening-primrose oil and placebo. In the low-dose groups (A and D) itch was the only symptom which responded better to evening-primrose oil than placebo. In the high-dose groups (B, C, and E) the patients’ assessments showed that the evening-primrose oil was significantly superior to the placebo with regard to itch, scaling, and general impression of severity	no side-effects were noted
12	Breth-jones [27]	16 weeks				At 16 weeks, the mean (SE; number of patients) improvements in Leicester scores were 8–48 (285; 33) for patients on epogam, 2–54 (289; 35) for patients on efamol marine, and 7–15 (2 88; 34) for those on placebo. On neither active regimen was mean improvement significantly different from placebo at 16 weeks (p = 074 for epogam, p = 0–26 for efamol marine). The only significant differences were in favour of placebo over efamol marine for responses of erythema and cracking	nausea, diarrhoea
13	Whitaker [28])	24 weeks After 16 weeks both groups were washed out for 8 weeks	IgE → EPO: 7 (255–1000 KU/I), Placebo: 7 (192–1000 KU/I)			At the end of active therapy, no statistical difference could be shown between 2 patient groups. at the end of 24 weeks, patients in EPO group, showed statistical difference in all paramteres while the placebo group showed constant statistical improvement of overall evaluation, redness, cracking and dryness
14	EBDEN [29]	8 weeks				There was no effect of Efamol capsules on the control of asthma. There was no statistically significant difference in the mean morning or evening peak expiratory flow rates for the last fourteen days of each treatment period. There was no statistically significant difference for a similar period in the symptoms score or daily inhaled bronchodilator usage. Similarly, there was no statistically significant difference in the histamine challenge value	No side effects were noted from treatment with Efamol
15	Hederos [30]	16 weeks	IgE (kU/l) in eczema → EPO:322, Placebo: 422			Asthma: This study found no clinical effect on peak expiratory flow or overall asthma response, neither with placebo nor with Epogam/Eczema: Both groups of patients were substantially improved with respect to baseline but no significant differences between groups were observed. No significant differences between the treatment groups were shown in the use of steroid ointments, classified by the most potent class of steroid used, although there with time in the Epogam group. highly significant increases in the concentrations of DGLA and arachidonic acid (metabolites of GLA) in the Epogam group but no change in the placebo group. The routine haematological and biochemical analyses showed only one significant difference between treatments and that was for urate, but all serum urate concentrations remained within the normal range	Five patients receiving Epogam reported five adverse events and six patients in the placebo group reported seven adverse events. None of these were considered serious, and only one in each group was considered to be of possible effect
16	Blommers [31]	6 months				The decrease in days with pain was 12.3% for evening primrose oil and 13.8% for its control oil (P = 0.73); the decrease in days with pain was 15.5% for fish oil and 10.6% for its control oil (P = 0.28)	Gastric, Abdominal, Skin, Increase in body weight
17	Goyal [32]	four menstrual cycles				The mean baseline breast pain score (NDBP) was 22 (on a scale of 0–56), which was similar across treatment groups. Twenty-five percent of patients had moderate mastalgia at baseline, while 75% had severe mastalgia. By the end of cycle 4, mean scores had decreased to 13–15, a reduction from baseline of approximately 35% (Table 3). There were no statistically significant differences among the four treatment groups. During the open treatment phase, all groups showed a further statistically significant improvement. By the end of cycle 12, mean scores had decreased to 8–11. This constituted an overall reduction from baseline of approximately 58%. The profile of change during the open phase was comparable across the four treatment groups	Digestive system disorders, respiratory system disorders, body in general—general disorders, reproductive system disorders, musculoskeletal system disorders, skin disorders
18	Pye [33]	6 months	Overall, a grade I or II response was achieved in 165 (77%) of the 215 patients with cyclical mastalgia (danazol 70%, bromocriptine 47%, evening-primrose oil 45%, progestagens 15% Overall, a grade I or II response was achieved in 29 (44%) of the 66 patients with non-cyclical mastalgia (danazol 31%, bromocriptine 20%, evening-primrose oil 27%, progestagens 9%			Effective
19	Qureshi [34]	three months to 1 year. (over a period of one year)				Results showed that out of 25 patients treated with OEP, 64% had a clinically significant response after three months of treatment, compared with 92% with topical NSAIDs	abdominal bloating, nausea, weight gain, headache, depression, giddiness, rash and bad taste
20	Nasri [35]	12 weeks	GSH (µmol/L) → EPO: 563.6 ± 138.4, Placebo: 470.5 ± 106 MDA(µmol/L) → EPO:2.1 ± 0.5, Placebo: 2.3 ± 0.8	GSH (µmol/L) → EPO: 626.3 ± 125.5, placebo: 469.8 ± 106.7 MDA(µmol/L) → EPO: 1.7 ± 0.4, placebo: 2.8 ± 1.6		significant increases in serum 25-hydroxyvitamin D (25(OH)D) (+ 10.7 ± 8.4 vs. − 0.5 ± 1.6 ng/mL, p < 0.001) and plasma total glutathione (GSH) (+ 62.7 ± 58.0 vs. − 0.7 ± 122.7 µmol/L, p = 0.01), while there were significant decreases in triglycerides (− 7.3 ± 23.8 vs. + 6.9 ± 26.3 mg/dL, p = 0.03), very low-density lipoprotein (VLDL) cholesterol levels (− 1.5 ± 4.7 vs. + 1.4 ± 5.3 mg/dL, p = 0.03), total/high-density lipoprotein cholesterol ratio (− 0.3 ± 0.4 vs. − 0.02 ± 0.4, p = 0.02), and malondialdehyde (MDA) concentration (− 0.4 ± 0.4 vs. + 0.5 ± 1.8 µmol/L, p = 0.008)	No side effects were reported following supplementation throughout the study
21	Farzaneh [36]	6 weeks				The percent of improvement in The frequency, severity and duration of hot flushes in the evening primrose group were 39, 42 and 19% compared to the placebo group, respectively 32, 32 and 18%. Although all three symptoms of hot flashes improved in the evening primrose arm, only the severity was significantly better in this arm compared to the placebo group (P < 0.05)
22	Gateley [37]	4 months (4 months EPO/ 2 months placebo and then 2 months EPO)				In the patients with cyclical mastalgia, the proportions of the esters of the saturated fatty acids, palmitic and stearic acid, were significantly elevated. The proportions of the esters of the polyunsaturated EFAs, linoleic, dihomo-y linolenic (DGLA) and AA, were significantly reduced. The differences in the patients with non-cyclical mastalgia were in the same direction, but only the reduced proportion of AA was significant. Evening primrose oil produced a significant increase in the proportion of DGLA, the metabolite of GLA, after 2 and 4 months of treatment
23	Gateley [37]	12 months				Treatment with evening primrose oil produced an immediate significant increase in the proportion of DGLA, which returned to the pretreatment proportion 4 months after completing treatment. There was a gradual increase in the proportion of arachidonic acid, which became significant after 12 months and was maintained 4 months after completing treatment. The proportion of the saturated fatty acid palmitic acid fell gradually, the difference becoming significant at 12 months. Treatment with placebo led to similar changes in arachidonic and palmitic acid to those seen in the group treated with evening primrose oil, but no change in DGLA during treatment	-
24	Gupta	12 weeks (4 weeks baseline washout period, treated for 6 weeks, followed by a 2 weeks.)	CRP → EPO:3.56 ± 1.64, placebo: 4.17 ± 2.95 MDA (µmol/L) → EPO:4.58 ± 2.08, Placebo: 4.41 ± 2.19 SOD(U/gHb) → EPO: 982.20 ± 191.28, placebo: 978.02 ± 236.61 GPX(U/gHb) → EPO: 74.19 ± 32.2, Placebo: 52.29 ± 29.91	CRP → EPO:3.28 ± 1.57, placebo: 4.50 ± 2.96 MDA (µmol/L) → EPO: 4.18 ± 1.95, placebo: 4.71 ± 2.12 SOD(U/gHb) → EPO: 953.97 ± 188.66, placebo: 1033.63 ± 244.83 GPX(U/gHb) → EPO: 66.47 ± 29.44, placebo: 60.10 ± 28.91		significant reductions in LDL cholesterol (LDL-C; -17.33% of baseline, P < 0.001) and total cholesterol (TC; -13.38% of baseline, P < 0.0001) values were observed during the experimental treatment period. producing product. This treatment also led to a decrease in the levels of C-reactive protein (CRP), malondialdehyde (MDA) and superoxide dismutase (SOD), which are indicators of oxidative stress	-
25	Ishikawa [38]	16 weeks	Apo A-1 (mg/dl) → EPO:132 ± 12, Placebo: 132 ± 16 Apo A-2 (mg/dl) → EPO: 38.1 ± 6.5, placebo: 38.1 ± 8.1 Apo B (mg/dl) → EPO: 142 ± 37, placebo: 159 ± 17 Apo C-2 (mg/dl) → EPO: 6.3 ± 2.4, placebo: 6.7 ± 2.3 Apo C-3 (mg/dl) → EPO:13.6 ± 5.7, placebo: 14.2 ± 5.3 Apo E (mg/dl) → EPO: 6.7 ± 1.5, placebo: 6.9 ± 2.2			a significant decrease in low density lipoprotein-cholesterol and plasma apolipoprotein B compared with the levels observed during safflower oil administration. Our results confirmed that EPO is effective in lowering low density lipoprotein in hypercholesterolemic patients	–
26	JENKINS [39]	12 months	-			After 12 months there was no significant difference in mean serum AlT between the groups nor in the number of patients with AlT levels within the normal range. One of the 10 patients in the treatment group showed histological improvement, but seven showed no change and two deteriorated. This contrasts with the patients receiving placebo, of whom four showed spontaneous histological improvement and five no change	No side effects were seen
27	Khoo [40]	6 months	-			There was no evidence of a difference between total PMS scores of the active and placebo groups, the mean difference being—0.026 with a standard error of 1.144 (test statistic from paired t-test = 0.02; 37 df; P = 0.982). Similarly, the two treatment groups did not significantly differ in their scores for psychological (mean [SE) = 0.447 [0.630)), fluid retention (0.211 [0.422)), breast (- 0.053 [0.410)), or menstrual symptoms (0.053 [0.258)). The test statistics are, respectively,—0.71, 0.50,—0.13, 0.20 (37 df; P = 0.482, 0.621, 0.898, 0.840)	Had no toxicity
28	Kokke [41]	6 months				improved symptoms and overall lens comfort in female patients with contact lens-related dry eye. Supplementation also caused a significant increase in tear production, as defined by tear meniscus height. It is reasonable to assume that the observed clinical improvement is primarily due to the documented anti-inflammatory effects of these EFAs
29	Laivuori [42]	31–36 weeks	-keto-PGF,,, 2,3-dinor-6-keto-PGF,,)/ (TXB2, 2,3-dinor-TXB,)			Supplementation of the diet with primrose or fish oil caused no changes in the production of PGI2, or TXA2 metabolites. The dietary supplementation appeared to have no effect on blood pressure or on other clinical variables, such as proteinuria and oedema
30	MOODLEY	2 weeks				No significant differences were found between the groups in respect to perinatal outcome, blood pressure lowering effect and haematological indices	-
31	Makrides [43]	6 weeks				Supplementation of infant formula with FO (0.36% total fatty acids as DHA) resulted in DHA levels being elevated above those of breast-fed infants at 16 and 30 weeks
32	Manthorpe [44]	3 weeks				Efamol/Efavit significantly improves the Schirmer-I-test in patients suffering from primary Sj6gren's syndrome (]'he Schirmer-I-test improved significantly during Efamol treatment while the P-values for the other tests did not reach the 0.05 level.). It has been suggested that the effect of Efamol is due to an insufficient amount of unsaturated fatty acids in the different tissues	Sudden universal flushing which usually began in the face and throat, sensation of heat, increase in pulse frequency and fear
33	OLIWIECKI [45]	28 weeks (placebo all patients first 4 weeks)				LAS scores for active and placebo-treated groups were compared at each visit. No significant difference was seen in the scores for erythema or scaling, e no significant differences between the active and placebo groups in the scores for itch, redness, anxiety and depression, no significant difference in plaque thickness and transepidermal water loss between the active and placebo-treated groups	-
34	Theander	6 months				No statistically significant improvement was found in fatigue assessed by Visual Analogue Scale (VAS) or in the time needed for sleeping/resting during a 24-h period. No differences were found between the treatment and placebo group. The same applies to the secondary endpoints: no differences in VAS for eye and mouth dryness or pain, no significant changes in Schirmer-1-test, van Bijsterveld score, unstimulated whole sialometry (UWS), or use of artificial tears or analgesics	mild gastrointestinal some patients complained about weight gain
35	Ka ´zmierska [46]	9 months				Compared to isotretinoin treatment, isotretinoin treatment combined with EPO had a positive effect on TCH concentrations (mean: 198 vs. 161, p < 0.001), LDL (95.9 vs. 60.2, p < 0.001), HDL (51.0 vs. 48.0, p < 0.001), TG (114 vs. 95.0, p < 0.001), ALT (24.0 vs. 22.0, p < 0.001), and AST (28.0 vs. 22.0, p < 0.001), but had no effect on the energy and ingredient content of the diets (p > 0.05) after treatment	No side effects were reported
36	Oxholm [47]	16 weeks				the results from Schirmer-I test, break-up time and van Bijsterveld score, improved significantly during Efamol treatment when compared with Efamol start-values. The GLA metabolite and prostaglandin-El (PGE,) precursor dihomogammalinolenic acid (20: 3116, DGLA) increased both in plasma and in erythrocytes) during treatment with Efamol. No correlations between objective ocular and oral status and DGLA values in plasma or erythrocytes were found	transient nausea and softening of stools: 3 patients
37	Iran/Soheila Rezapour-Firouzi a,b, ∗ , Seyed Rafie Arefhosseini	6 months	IL-4 (pg/ml) → A: 0.56 ± 0.20, B: 0.50 ± 0.50, C: 0.81 ± 0.12 IFN-γ → A: 0.56 ± 0.04, B: 0.22 ± 0.06, C: 0.35 ± 0.23, IL-17 → A: 0.51 ± 0.09, B: 0.26 ± 0.11, C: 0.51 ± 0.03	IL-4 (pg/ml) → A: 0.70 ± 0.17, B: 0.41 ± 0.14, C: 0.96 ± 0.11 IFN-γ → A: 0.24 ± 0.04, B: 0.39 ± 0.06, C: 0.30 ± 0.14, IL-17 → A: O.39 ± 0.04, B: 0.41 ± 0.20, C: 0.45 ± 0.15		combination of HSO and EPO as a dietary supplement in a daily dose of 18—21 g/day over a period of 6 months showed immune-modulating effects in our study with RRMS patients resulting in significant improvements of the EDSS score and the relapse rate compared to a control group receiving 18—21 g olive oil per day. Small changes in the levels of the cytokines were observed in all groups and were rather consistent with the clinical outcomes: IL-4 increased significantly in group A and C, IFN-γ decreased significantly in group A and increased in group B. The Mizadj score increased in both active treatment groups significantly. Further research must show the properties of this score and its the correlation with the clinical data	-
38	Rezapour-Firouzi [48]	6 months	-			There was no significant difference in the study parameters at baseline. Serum levels of liver enzymes (GGT, AST, and ALT) were serially monitored. Intervention was associated with liver function alteration in three groups. Significance decreased in EDSS score and the levels of liver enzymes were found in groups A and C, whereas elevated serum liver enzymes and EDSS score were observed in group B after the intervention	-
39	Rezapour-Firouzi [49]	6 months	-			After 6 months, significant improvements in EDSS and functional score were found in the groups A and C while EDSS and pyramidal score showed significant increase in group B. Alteration of biochemical parameters showed improvement in groups A and C whereas there was worsening condition for group B after the intervention. (the observed reduction of D6D was a consequence of the well- described effects of this type of intervention, and that an increase in PUFAs and reduction in expression of sPLA2 key enzymes caused a decrease in mean EDSS. Surprisingly, altering PUFAs rate causes a decrease in sPLA2 expression, in particular, in the co-supplemented oils and Hot-natured diet group)	-
40	Rezapour-Firouzi [50]	6 months	IL-4 (pg/ml) → A: 0.58 ± 0.50, B: 0.50 ± 0.50, C: 0.81 ± 0.87 IFN-γ → A: 0.26 ± 0.04, B: 0.22 ± 0.06, C: 0.35 ± 0.23	IL-4 (pg/ml) → A: 0.69 ± 0.69, B: 0.41 ± 0.14, C: 0.95 ± 0.91 IFN-γ → A: 0.24 ± 0.04, B: 0.24 ± 0.06, C: 0.31 ± 0.14		There was no significant difference in the study parameters at baseline. After 6 months, EDSS, Immunological parameters and the erythrocyte cell membrane with regard to specific fatty acids showed improvement in the group A and C, whereas there was worsening condition for the group B after the intervention. We concluded that Hot-nature dietary intervention with co-supplemented hemp seed and EPOs caused an increase PUFAs in MS patients and improvement in the erythrocyte membrane fatty acids composition. This could be an indication of restored plasma stores, and a reflection of disease severity reduction	-
41	Vaddadi [51]	8 months (32 weeks)				The efficacy/anti-dyskinetic effect of EFA supplementation was marginally significant but not clinically significant. However, active treatment produced highly significant improvements in total psychopathology scores and schizophrenia subscale scores and significant improvements in memory	No side effects
42	VEALE [52]	12 months	ESR, CRP, TXA2			all measures of skin disease activity including severity, percentage of affected body and itching remained unchanged by Efamol Marine. NSAID requirement remained the same between both treatment groups. In addition, no changes were shown in arthritis activity as measured by duration of morning stiffness, Richie joint index, number of active joints, ESR and CRP. However, an increase in serum TXB2 was observed in the active group in the placebo phase. Furthermore, there was a decrease in leukotriene B4 production during the active phase followed by a significant increase during the placebo phase, suggesting some in vitro documented anti-inflammatory effects	-