Abstract

1. Introduction¹

Hibiscus sabdariffa L. (HS) (Malvaceae) tea is in widespread use across the world as a beverage and as a treatment for hypertension and hyperlipidemia. Two systematic reviews have been published on the effectiveness of HS for the treatment of hypertension [1, 2]. However Ngamjarus and colleagues [2] excluded all randomized clinical trials (RCTs) as being of too low quality, and Wahabi and colleagues [1] established the quality of studies using the Jadad scale, a scale which focuses exclusively on randomization, blinding and participant withdrawals [3–6]. Both reviews determined that the evidence available at the time of review was inconclusive.

However, subsequent to the publication of these two previous reviews, expanded criteria allowing for a more comprehensive evaluation of the totality of evidence related to the medicinal use of botanicals have been proposed by Fonnebo and colleagues [7]. This review applies these updated and expanded criteria to assess data related to the use of HS for hypertension, including data from a high quality study published subsequent to earlier reviews [8]. Furthermore, to obtain a more complete view of potential protective effects of HS as relates to cardiovascular disease, evidence related to HS effects on cholesterol metabolism are also reviewed. These data are reviewed in the context of ethnomedicinal information on HS use, preparation, and dosage and updated phytochemical, pharmacological, and toxicological information on HS, which was last reviewed by Ali and colleagues in 2005 [9].

The objective of this review is to:

• Examine the evidence of the effectiveness of HS on cardiovascular risk factors based on ethnomedicinal, safety and toxicity, pharmacological, phytochemical information

2. Methods

3. Ethnomedicinal Uses and Preparation

HS is consumed as a beverage in the United States [8], Mexico [11, 13, 16], Nigeria and other West African countries [21–25], Egypt [26], Iran [10, 14, 18], India [17, 27, 28], Thailand [29], and Tawian [15, 30, 31], among other countries. Ethnomedicinal studies have reported the use of HS for the treatment of various cardiovascular risk factors including hypertension in Egypt, Jordan, and Trinidad and Tobago [32–35], hypotension in Jordan and Iraq [34, 36], hyperlipidemia in Jordan, Greece, Brazil, and Trinidad and Tobago [33, 35, 37, 38], and obesity in Iraq, Greece, and Brazil [36–38].

The flowers, or more specifically the calyxes, are typically prepared using an aqueous decoction or infusion [32, 33, 36, 38]. However, the Bedouins in the North Badia region of Jordan use the leaves, as well as the flowers, and they drink the infusions hot when treating high blood pressure and cold when treating low blood pressure [34]. In Trinidad and Tobago only the leaves are used to treat high blood pressure and the flower and seeds are used to treat high cholesterol [35]. Dosing was only described in 1 [36] of the 7 ethnobotancial studies reviewed. Mati and colleagues [36] discovered that herbalists in the Kurdistan Autonomous Region of Iraq recommend drinking 1 cup/day of an infusion of 1 tsp (1/2 tsp when ground) of HS flowers in 1 cup warm water for the treatment of hypotension and 2 cups/day of a decoction of 2 tsp of the HS flowers in 1/2 L of water or 1 cup/day of a decoction of 50 g in 2 cups of water for the treatment of obesity.

4. Phytochemical Properties

The main compounds found in HS flowers are organic acids, mainly citric and malic acids, anthocyanins, a myriad of flavonoids and glycosides, and fiber [9, 39–41]. The calyxes have the same organic acid and anthocyanin constituents, but the presence of flavonoids and glycosides is minimal [9]. Anthocyanins, particularly delphinidin-3-sambubioside and cyanidin-3-sambubioside, are generally believed to be the active constituents responsible for the antihypertensive, antioxidant, and hypocholesterolemic effects of HS, possibly because they are found in high relative quantities in aqueous extracts [8, 11, 13, 16]. However, Yang [42] compared a polyphenol rich (74%) extract containing protocatechuic acid (24.2%), catechin (2.7%), gallocatechins (2.4%), caffeic acid (19.9%), and gallocatechin gallates (30.0%) with an aqueous extract of HS containing anthocyanins (2.5%), polyphenolic acid (1.7%) and flavonoids (1.4%) and determined that the phenol rich extract exhibited a greater ability to decrease total cholesterol and LDL-C cholesterol and increased HDL-C cholesterol dose-dependently suggesting the importance of polyphenols in inducing anti-cholesterol effects. Hibiscus acid may also be playing a role in lower blood pressure and cholesterol [43].

The plant parts used, the color of the parts, the harvesting practices and the preparation method greatly influence the volatile composition of the extract and influence dosing [9]. The HS varieties with deeper red calyxes exhibited greater antioxidant activity as compared to lighter red or white varieties [44, 45]. Greater antioxidant activity was found in flowers that were harvested at 35 days after flowering as compared to less mature flowers [45]. Ethanol extractions of calyxes exhibited the highest antioxidant activity as compared to ethanol extractions of leaves and aqueous extractions of both plant parts [28]. However, aqueous extractions are appropriate for studies interested in testing the effectiveness of traditional preparation practices and capturing the broad public health implications of this herbal treatment.

Very little research has been done on the bioavailability of HS extract. McKay and colleagues [8] provide the only exception in their clinical trial where they brewed HS tea by steeping 1,250 mg of dried HS in 240 mL of boiled water, administering one such serving three times a day. No anthocyanins were detected in the urine within one hour of consumption of this HS tea, which contained 22 mg gallic acid equivalents (GAE) total phenols, 7 mg cyanidin glucoside equivalents (CGE) total anthocyanins, 4 mg CGE delphinidin-3-sambubioside, 0.02 mg CGE cyanidin-3-sambubioside, and 1950 µmol trolox equivalents/g oxygen radical absorbance capacity (ORAC).

5. Safety and Toxicity

Studies carried out in animals and humans have primarily demonstrated either no change or decreases in measures related to function of the liver (AST and ALT liver enzymes [16, 46, 47]) or kidney (creatinine [16, 18, 22, 23, 31, 46, 48], blood urea nitrogen [18, 31], and urea [16]) function (Table 1). However, at doses of 300 mg/kg/day of HS over a 3 month period, an adverse effect on liver enzymes was observed, suggesting that at very high doses the extract could be hepatotoxic [46]. Uric acid levels were reported to be elevated in rodents given extremely high doses of HS, a potential adverse effect that could exacerbate or contribute to the development of gout [23].

HS extracts administered at 500 mg/kg/day over the course of 3 weeks exhibited diuretic properties in hypertensive animal models. HS consumption in most cases had no significant effect on electrolytes, including magnesium, sodium, potassium, and/or chlorine/chloride [11, 13, 18, 22, 49], although sodium [13] and chlorine levels [11] in humans increased statistically significantly from baseline to final measurement at 30 days of receiving HS extract. The diuretic behavior of HS extract in these two studies has been compared to the potassium sparing group of diuretic pharmaceuticals, such as Spironolactone or aldosterone antagonists [11, 13].

A few other studies among animals suggest that HS extracts have a low degree of acute toxicity with the median lethal dose (LD50) ranging from 2,000 to over 5,000 mg/kg [23, 46, 49]. In contrast, one studied showed that doses as high as 4,600 mg/kg can be administered for several months in an animal model with no report of mortality, although negative effects on testes and sperm count were found [50]. The variation in these findings may be due to the type of solvents used for extraction, the method and length of administration and the variety of HS used [46].

Herb-drug interactions between HS and hydrochlorothiazide (HCTZ) [49], a commonly prescribed diuretic medication, and acetaminophen [51], an antipyretic-analgesic over-the-counter medication, were examined. Co-administration of HS extract (40 mg/kg) and HCTZ (10 mg/kg) in rats caused a significant increase in the volume of urine excreted, but electrolyte levels were more similar to controls than HCTZ alone [49]. Pharmacokinetics measurements in rabbits suggest that co-administration of HS (20–40 mg/kg) and HCTZ (10 mg/kg) may result in retention of HCTZ, less clearing of HCTZ from the body with increased doses of HS, and slower HCTZ elimination. These results suggest a possible herb-drug interaction and HS should not be used in conjunction with HCTZ. The only pharmacokinetic effect of consumption of HS in adult males before taking acetaminophen was enhanced elimination of the acetaminophen [51]. Based on these findings, acetaminophen should be taken 3–4 hours before drinking HS to avoid shorten its therapeutic effect.

6. HS in the Treatment of High Blood Pressure

7. HS in the Treatment of Elevated Cholesterol

8. Quality of RCT Reporting

The studies consistently reported the CONSORT items relevant to all RCTs with scores ranging from 59% [15] of the items reported to 96% [8] (Table 6). The items 1–6 and 12 were reported by most RCTs and included information on eligibility criteria for participants, a description of the intervention, outcome measurements and statistical methods (item 12). Items from the results section including participant flow (item 13), baseline data (item 15), and results from analyses (items 17 and 18) were also generally included. In addition all discussion items, including interpretation of results (item 20) within the context of current evidence (item 22) and external validity (item 21). However, there were several areas where reporting could be improved, including sample size (item 7), randomization sequence allocation (item 8), allocation concealment (item 9), and implementation (item 10), blinding (item 11), recruitment (item 14), numbers analyzed (item 16), and adverse events (item 19).

More specifically, most studies did not make clear the type of RCT being conducted and in many cases there were study design problems. In several RCTs black tea was used as the comparator, as opposed to a placebo, making the results difficult to interpret because of the active pharmacological properties of black tea [10, 12, 14, 18]. McKay and colleagues’ [8] in the only placebo-controlled trial to date provided a notable exception to this trend by using a placebo drink that was non-active and is used in the beverage industry to mimic the flavor of HS tea in commercially prepared drinks. In some comparative effectiveness trials it was difficult to compare effectiveness between treatments because the medication was not administered as directed by doctors [11], whereas other trials provided realistic comparators [13, 16]. The results from the study on dose response are difficult to interpret because the baseline values for total cholesterol differed substantially between groups [15].

Additionally, there were several problems specific to the cholesterol RCTs. Differences between groups were impossible to assess because none of the studies included effect sizes or statistical analyses of the between-group differences [14–18]. Another problem with most of the cholesterol trials was short study duration with 4 trials lasting 15 days [18] to 30 days [14–16] and only one trial of a longer 90 day duration [17]. In general, lipid profiles can take up to 2 months to reflect meaningful change in patients given statin medication or modifications to their diet and lifestyle [55, 56]. The hypertension trials selected patient populations with mild to moderate hypertension [8, 11–13] with only one study providing the additional condition of diabetes [10], whereas the patient populations in the cholesterol trials had an array of conditions, many of which did not include elevated cholesterol [14, 16, 18], making it difficult to assess the effectiveness of HS in treating hyperlipidemia.

The quality scores for items specific to the herbal intervention were much lower, ranging from 28% [12] to 67% [8] for the hypertension RCTs and from 33% [18] to 65% [15, 16] for the cholesterol RCTs. Reporting was particularly lacking in the herbal description in the title or abstract (item 1), description of how traditional theories and concepts were maintained, including traditional preparation and dosing practices (item 3), all aspects of the intervention (items 4a, 4c–4f), except characteristics of the herbal product (item 4b), concomitant medications (item 15), interpretation in the light of the product and dosage regimen used (item 20) and how the herbal product and dosage regimen used relates to self-care (item 21).

There were also several problems with the preparation of HS. Many of the studies did not report the part of the plant that was used in the preparation. Kuriyan and colleagues [17] used the leaves in their extract without explanation, whereas the calyxes are most commonly used in HS preparations. In addition, the amount of HS used in preparations and the dose administered varied greatly with Mohagheghi and colleagues [18] choosing to use an extremely small amount of HS calyxes in the preparation per dose and many of the studies failing to include any measure of marker constituents. The absence of information related to product content and the method of preparation and the lack of uniformity of extracts made it difficult to compare findings between studies. In addition, the lack of information regarding ethnobotanical use made it difficult to determine the relationship between the studies and traditional therapeutic use.

9. Biological Mechanisms

In vitro and in vivo studies focused on mechanism of action have determined several potential mechanisms of the HS extracts that may explain the hypotensive activity, including (1) vasodilation mediated through endothelium-derived relaxant pathways and inhibition of calcium influx [9, 57], (2) ACE inhibition [9] by the stimulation of new vessel formation and a reduction of myocardial mass [52] or anthocyanins competing with the substrate for the active site [58], (3) decrease in blood viscosity through cyclooxygenase inhibitory activity [44], and (4) inhibition of adipocyte differentiation through the modulation of PI3-K/Akt and ERK pathway [59].

Other potential mechanisms have been tested to explain the positive impact of HS extract on cholesterol metabolism. For example, cholesterol biosynthesis may be reduced by inhibiting HMG-CoA reductase [42, 60]. Decreases in LDL-C may be the result of the inhibition of triacylglycerol synthesis by hibiscus acid racemization [43]. The positive effects of the extract in diabetic animal models may be partially the result of the reduction in the expression of CTGF and RAGE [30]. Additionally, although not directly related to the reduction in cholesterol but beneficial for improving cardiovascular risk factors, HS may hinder atherosclerosis and improve vasoreactivity through (1) impediment of the formation of macrophage-derived foam cells [61] and/or (2) inhibition of LDL-C oxidation due to antioxidant effects of the extract [25, 28, 29, 31, 53, 54].

10. Conclusions

There are many strengths and limitations to the array of evidence considered in this review. Ethnomedicinal studies provide evidence for the widespread use of a tea made with HS calyxes to treat hypertension and hyperlipidemia, but these studies provide little guidance for animal and human studies through their lack of attention to cultivation, preparation, and consumption patterns. HS extracts are generally considered to have a low degree of toxicity. Studies demonstrate that HS consumption does not adversely effect liver and kidney function at lower doses, but may be hepatotoxic at extremely high doses. In addition, electrolyte levels generally are not effected by ingesting HS extracts despite its diuretic effects.

Animal studies have consistently shown that consumption of HS extract reduces blood pressure in a dose dependent manner. They have also shown that total cholesterol, LDL-C, and triglycerides were lowered in the majority of normolipidemic, hyperlipidemic, and diabetic animal models, whereas HDL-C was generally not affected by the consumption of HS extract.

The daily consumption of HS calyx extracts significantly lowered SBP and DBP in adults with pre to moderate essential hypertension and type 2 diabetes. In addition, HS tea was as effective at lowering blood pressure as Captropril, but less effective than Lisinopril. Over half of the RCTs showed that daily consumption of HS tea or extracts had a favorable influence on lipid profiles including reduced total cholesterol, LDL-C, triglycerides as well as increased HDL-C. Regrettably many of the RCTs were of low quality and did a poor job characterizing the HS extracts and utilized a form that is not widely consumed making it difficult to determine the amount of public health benefit related to HS tea consumption. McKay and colleagues [8] provide a notable exception with their high quality placebo-controlled trial. As the findings related to the effects of HS on blood pressure from lower quality studies are consistent with those of this high quality study, the totality of evidence suggests that HS consumption may have a public health benefit due to its anti-hypertensive effects.

Anthocyanins found in abundance in HS calyxes are generally considered the phytochemicals responsible for the antihypertensive and hypocholesterolemic effects, however evidence has also been provided for the role of polyphenols and hibiscus acid. A number of potential mechanisms have been proposed to explain the hypotensive and anticholesterol effects, but the most common explanation is the antioxidant effects of the anthocyanins inhibit LDL-C oxidation which impedes atherosclerosis, an important cardiovascular risk factor. Research on active compounds in HS and the mechanisms of action are still fairly nascent making it difficult to justify carrying out RCTs using anything other than the whole plant parts used in general practice.

This body of evidence interpreted together suggests that HS has great potential to reduce risk factors associated with cardiovascular disease and merits further study.

Acknowledgements

Footnotes

References