Evidence-Based Human Clinical Trials on Antidiabetic Herbal Remedies Commonly Used in the Middle East

TL;DR

This paper reviews clinical evidence for Middle Eastern herbs as potential treatments for type 2 diabetes.

Contribution

It provides a systematic analysis of randomized controlled trials and meta-analyses on five commonly used herbs in the region.

Findings

Nigella sativa and fenugreek improved blood sugar and lipid levels in patients.

Ginger and curcumin showed beneficial effects on metabolism and antioxidant activity.

Cinnamon was found to help with glucose transport and enzyme inhibition.

Abstract

Type 2 diabetes mellitus (T2DM) is a prevalent metabolic disorder with significant health and economic impacts. This review examined Middle Eastern herbs as alternative T2DM treatments in human randomised controlled trials and meta-analyses. A comprehensive PubMed search was conducted for human randomised controlled trials and meta-analyses on black seed (Nigella sativa), fenugreek (Trigonella foenum-graecum), ginger (Zingiber officinale), cinnamon (Cinnamomum cassia) and curcumin (Curcuma longa), with at least 6 human studies per herb. The results revealed that N. sativa and fenugreek improved glycaemic control and lipid profiles, while ginger regulated carbohydrate metabolism enzymes. Curcumin was found to control blood sugar and lipids through its antioxidant effects, although its bioavailability remains a challenge. Cinnamon enhanced glucose transport and enzyme inhibition. Notably, N. sativa demonstrated consistent positive effects across studies. These findings highlight the potential of medicinal herbs as alternative therapies in T2DM management, emphasising the need for further research in this field, considering relevant safety profiles.

Tables

Table 1.. Summary of evidence-based findings included in this review.11-1620232932363940424445506668-75

Botanical name	Key properties	Key diabetes-related findings of independent studies	Safety considerations
Black seed ( Nigella sativa )	Diuretic, antihypertensive, anticancer, immunomodulator, antimicrobial, analgesic and antioxidant.11	- Improved glycaemic and lipid profile.1220	- Low toxicity.25
		- Reduction in HbA1c in metabolic syndrome risk patients.13	- Contact dermatitis reported with topical use.26
		- Protection against diastolic dysfunction in uncontrolled T2DM patients.14
		- Effective supplementary therapy in insulin resistance patients.1516
		- Improvement in blood glucose, serum creatinine, blood urea and urinary protein levels in diabetic nephropathy patients.2324
Fenugreek ( Trigonella foenum-graecum )	Hypoglycaemic and antihyperlipidemic.27	- Reductions in FPG, TG and VLDL-C.	Generally safe in measured amounts.28
		- Improved blood glucose and HbA1c levels in T2DM patients.29
		- Reduction in the cumulative incidence rate of diabetes and improvements in lipid profile.32
		- Decrease in total cholesterol, TG and LDL-C, and increase in HDL-C.3334
Ginger ( Zingiber officinale )	- Antidiabetic effects by controlling key enzymes of carbohydrate metabolic pathways.35	- Improved glucose control, insulin sensitivity and blood lipid profile in T2DM patients.	Generally safe in measured amounts; may cause mild side effects; caution with anticoagulant medications.50
	- Anti-inflammatory, anticlotting and antioxidant effects.36	- Reduction in FPG and HbA1c, and improvement of insulin resistance.3940
		- Improvement in insulin sensitivity and lipid profile.4244
		- Improvement in insulin sensitivity and lipid profile in diabetic NAFLD patients.45
Cinnamon ( Cinnamomum cassia )	- Control of key carbohydrate metabolism enzymes and increased expression and translocation of GLUT transporters.5152	- Reduction in FPG levels and no significant change in HbA1c levels.5255	Generally safe in measured amounts. In excess, it may lead to liver damage, allergies and skin irritation.6263
	- Anti-inflammatory and antioxidant.51	- Reduction in FBG and HbA1c levels.53
		- Decrease in mean HbA1c levels.5458
		- Reduction in plasma glucose levels and HbA1c levels.56
		- Reduction in FBG.57
		- Lowering of HbA1C compared to medications alone.58
		- No significant effects on the glycaemic profile.59-61
Curcumin ( Curcuma longa )	- Active polyphenol of turmeric plant.64	- Improved overall lipid (TG and cholesterol) and lipoprotein (a) profile.70	Generally safe in measured amounts; however, it has bioavailability, due to low water solubility, permeability and clearance.69
	- Anti-inflammatory, antioxidant,65 wound healing, skin protection66 and genotoxicity protection.6568	- Decreased TG and hs-CRP levels and increased adiponectin levels.71
		- Reduction in hs-CRP and lipoprotein (a).72
		- Reduction in inflammation, oxidative stress, insulin and hs-CRP levels with nano-curcumin and EPA.73
		- Reduction in HbA1c levels and improvement in neuropathy scores.74
		- Decrease oxidative stress through a decrease in MDA levels, increase in TAC and GSH levels and upregulation of PPAR-γ and improvement in sleep quality and psychological status.75

Full text

1. Introduction

Type 2 diabetes mellitus (T2DM) is a chronic disease characterised by high blood sugar levels resulting from insulin resistance (IR). Fasting plasma glucose (FPG) and glycated haemoglobin (HbA1c) are 2 common T2DM diagnostic measures. According to the American Diabetes Association, an HbA1c level above 6.5% or an FPG level exceeding 126 mg/dL (7.0 mmol/L) is indicative of diabetes.^1^ Uncontrolled T2DM can lead to both microvascular and macrovascular complications. To manage early-stage T2DM, standard practices include dietary modifications, regular exercise and the use of hypoglycaemic drugs. Conventional treatment typically involves oral hypoglycaemic agents (OHAs) such as metformin, which decreases hepatic glucose production, and sulfonylureas, which stimulate insulin secretion. In more advanced cases, insulin therapy may be necessary to stabilise blood sugar levels. Monitoring blood glucose levels is essential for making timely adjustments to treatment plans.^1^ Additionally, complementary therapies, including herbal remedies, dietary supplements (vitamins and minerals) and other natural products, have demonstrated efficacy in combating diabetes and its associated complications. However, these treatments are often accompanied by side effects and can be costly.^2^ Conventional belief indicates that botanical herbs and their derivative compounds may offer a valuable alternative approach to managing diabetes, potentially with a more favourable side-effect profile. Nevertheless, there is a limited number of evidence-based studies that demonstrate their proven medicinal benefits.

Herbs have been used for centuries to treat various ailments in both Western and traditional Eastern medicine, such as traditional Chinese medicine, Ayurvedic medicine, herbal medicine and naturopathy. Globally, people rely on herbal remedies to address chronic and acute diseases, especially in developing countries.^3^ Herbal medicines are commonly administered in the form of teas, oils, liquids or dry extracts. Many pharmaceutical products, such as aspirin, morphine, digoxin and quinidine, have been extracted from plant sources.^4^ Herbal medicines are believed to be effective, affordable and safe, with fewer side effects than conventional medicine. However, safety concerns arise from unregulated consumption, which can lead to toxicity, allergic reactions or interactions with other medications.^5^ In developing countries, including those in the Middle East, traditional herbal remedies have been used for diabetes management for many years.^67^

Common herbal remedies used in the region include fenugreek (Trigonella foenum-graecum), cinnamon (Cinnamomum cassia), ginger (Zingiber officinale), curcumin (Curcuma longa) and black seed (Nigella sativa), all of which are believed to possess antidiabetic benefits.^8^

The use of antidiabetic herbs extends beyond their cost-effectiveness and perceived safety compared to conventional drugs and management strategies. Herbs are often perceived as natural and culturally acceptable remedies, especially in regions where traditional herbal medicine is an essential part of healthcare practices, including preventive measures. Despite the increasing popularity of herbal usage, there is a lack of comprehensive, evidence-based studies on antidiabetic herbs, resulting in critical gaps in current knowledge. It is essential to update the existing literature to address these gaps, establish a groundwork for future research on herbs that have demonstrated therapeutic efficacy and provide a valuable resource for advancing preventive and complementary approaches in diabetes management.

This review aimed to present evidence-based findings from randomised controlled human clinical trials that demonstrate the efficacy and potential therapeutic benefits of key herbal remedies used in the Middle East for diabetes management.

2. Methods

This review followed a descriptive approach that aimed to present findings, including both evidence supporting the use of these herbs and studies demonstrating limited or no effects. It synthesised a balanced overview of favourable outcomes, inconclusive and non-significant findings, as well as any safety concerns.

A comprehensive PubMed search was conducted to extract randomised controlled clinical trials and meta-analyses. The search strategy included specific keywords and search terms related to medicinal herbs used in the Middle East for managing diabetes. Inclusion criteria were defined to ensure the relevance and quality of the studies. Specifically, the criteria required evidence from a minimum of 6 human studies for each selected herb, ensuring a thorough evaluation. All studies included in this review focused on adult populations, aged 18 and above, with many extending into the 60–70 age range. This approach helped represent a broad spectrum of study participants and provides consistency in supporting the relevance to a typical adult demographic.

Studies were selected based on established clinical trial standards, which include randomisation, control groups and clearly defined outcome measures. Additionally, meta-analyses were incorporated to synthesise data from multiple studies, providing a more robust evaluation of the evidence.

The following search terms were used: herbs, Middle East, diabetes, glucose, insulin, ginger, Zingiber officinale, fenugreek, black seed, Nigella sativa, black cumin, cinnamon and Cinnamomum cassia. Inclusion criteria included only in vivo human studies that focused on commonly used Middle Eastern herbs for diabetes management. In vitro and animal studies were excluded.

3. Results and discussion

Common herbs in the Middle East that are utilised as potential therapeutic targets for diabetes management include black seed, fenugreek, ginger, cinnamon and curcumin [Table 1].

3.1. Black seed (Nigella sativa)

Black seed (N. sativa) is an annual herbaceous flowering plant that belongs to the Ranunculaceae family, the Nigella genus and the N. sativa species. The seeds of N. sativa are edible; it is known as ‘habat-ul-sauda’ in Arabic and black cumin in English.^9^ N. sativa is native to the Mediterranean region but is also cultivated in Russia, Turkey, Egypt, the Middle East and France. It is extensively distributed in tropical Africa.^10^ The black seed has been suggested to possess several therapeutic potentials such as diuretic, antihypertensive, anticancer, immunomodulatory, analgesic, antimicrobial, anthelmintic, anti-inflammatory, spasmolytic, bronchodilator, gastroprotective, hepatoprotective, renoprotective and antioxidant properties.^11^

Heshmati et al. conducted a randomised, double-blind, placebo-controlled trial involving T2DM patients aged 30–60 years.^12^ Participants received 3 g/day (1 g thrice daily) of either black seed oil or sunflower soft gel capsules for a duration of 12 weeks. The results showed that black seed oil significantly improved glycaemic status and lipid profile, evidenced by a notable decrease in fasting blood sugar, HbA1c, triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C) levels. Additionally, the researchers observed a reduction in insulin levels and IR, as estimated by Homeostatic Model Assessment for IR, along with an increase in high-density lipoprotein cholesterol (HDL-C) in the intervention group. However, after adjusting for confounding factors, these results were no longer statistically significant.^12^ Rachman et al. conducted a randomised, single-blind study to determine the efficacy of black seed oil combined with a hypoglycaemic agent to reduce HbA1c levels in patients with metabolic syndrome characterised by IR.^13^ The results indicated that administering 1.5 or 3 mL/day of black seed oil alongside a hypoglycaemic drug for 20 days resulted in a significant reduction in HbA1c levels among patients at risk for metabolic syndrome.^13^

Bamosa et al.'s blinded placebo-controlled clinical trial evaluated the effects of black seed supplementation on cardiac function in uncontrolled T2DM patients who were treated with OHAs. The test group received 2 g/day of powdered black seed for 1 year. The study demonstrated that HbA1c decreased significantly in the black seed-treated group. Additionally, the findings suggest that black seed supplementation may offer cardioprotective benefits for T2DM patients by improving left ventricular systolic function and potentially providing favourable effects on diastolic dysfunction.^14^ In another study, Bamosa et al. evaluated different dosages (1, 2 and 3 g/day) of black seed in 2 different studies.^1516^ In the first study, they assessed the impact of black seed on glycaemic control in T2DM patients. They reported that a dosage of 2 g/day resulted in significant reductions in FPG and HbA1c without major changes in body weight and without renal or hepatic side effects. They concluded that black seed may be considered a beneficial adjuvant to OHAs for T2DM patients.^15^ The second study assessed the impact of black seed on the lipid profile and concluded that black seed supplementation at a dosage of 2 g/day for 12 weeks caused a significant decline in total cholesterol (TC), TG and LDL-C, along with a significant elevation in HDL-C/LDL-C. Therefore, black seed may improve dyslipidaemia associated with T2DM and has potential protective effects against atherosclerosis and cardiovascular complications.^16^

Moustafa et al.'s randomised, open-label clinical trial investigated the efficacy of black seed compared to metformin in patients newly diagnosed with T2DM.^17^ The study evaluated various factors, including glycaemic indices (FPG, 2-hour postprandial glucose, HbA1c, IR, secretory function and insulin sensitivity), lipid profiles (TC, LDL-C, HDL-C and TG), liver and kidney functions (aspartate transaminase [AST] and alanine aminotransferase [ALT]), total antioxidant capacity (TAC), body weight, waist circumference (WC) and body mass index (BMI). Measurements were taken at the onset of the study and after the treatment period. This study's findings indicated that a daily dose of 1.35 g of black seed was less effective than metformin in reducing FPG, 2-hour postprandial glucose and HbA1c levels, and in enhancing secretory function. However, black seed was comparable to metformin in significantly decreasing body weight, WC and BMI. Additionally, black seed exhibited similar effects to metformin in controlling fasting insulin levels, IR, ALT, lipid profiles and TAC. Notably, metformin led to a significant increase in AST and creatinine levels, which was not observed in the black seed group.^17^ Furthermore, black seed was found to lower TC, mean arterial pressure and heart rate in a 1-year follow-up longitudinal study, although the study was not randomised.^18^

Kaatabi et al.'s longitudinal study explored the long-term glucose-lowering effects of black seed in T2DM patients who were using oral hypoglycaemic drugs over a 1-year period.^19^ The study demonstrated a significant decrease in FPG, HbA1c and lipid peroxidation parameters, such as thiobarbituric acid reactive substances, in the black seed group. Conversely, there were significant elevations in antioxidant parameters, including TAC, glutathione (GSH) levels and superoxide dismutase activity. Thus, long-term supplementation with black seed was found to improve glucose homeostasis and enhance the antioxidant defence system in T2DM patients receiving oral hypoglycaemic drugs.^19^

A double-blind, randomised clinical trial conducted by Kooshki et al. aimed to determine the impact of black seed oil on various cardiovascular risk factors in patients with T2DM.^20^ For 8 weeks, the intervention group received 2 capsules containing 1 g of black seed oil extract, whereas the control group received placebo capsules. The results indicated that the black seed oil group experienced a significant decrease in FPG, TG, TC and LDL-C, along with a significant increase in HDL-C. Additionally, serum levels of high-sensitivity C-reactive protein (hs-CRP) and malondialdehyde (MDA) decreased significantly, indicating a reduction in systemic inflammation and lipid peroxidation.^20^

Another randomised, double-blind, controlled clinical trial was conducted by Hadi et al. to determine the effects of black seed oil extract on cardio-metabolic risk factors in T2DM patients.^21^ The intervention group received 2 soft gel capsules containing 0.5 g of black seed oil extract per day for 8 weeks. The black seed-treated group showed a significant decrease in FPG, HbA1c, TG, TC, LDL-C, BMI, WC, systolic blood pressure (SBP) and diastolic blood pressure compared to the placebo-treated group. However, the black seed-supplemented group did not show a significant change in IR or HDL-C levels.^21^ In another study, the antioxidant effects of N. sativa were evidenced by significant reductions in oxidative stress parameters, including serum MDA and nitric oxide levels.^22^

Regarding the safety and toxicity of black seed consumption, 2 randomised clinical trials explored its protective effects and safety in patients with T2DM.^2324^ In the first study, participants were randomly assigned to 2 groups. The control group received standard conservative management for chronic kidney disease, which included an alpha-keto analogue, while the intervention group received the same management supplemented with N. sativa oil (2.5 mL once daily) for 12 weeks. The results showed that the test group experienced reductions in blood glucose, blood urea, serum creatinine and 24-hour total urine protein, along with increases in haemoglobin, 24-hour total urine volume and glomerular filtration rate (GFR). These findings suggest that N. sativa oil supplementation combined with an alpha-keto analogue is both effective and safe in slowing the progression of diabetic nephropathy.^23^

The second study included patients with chronic kidney disease at stages 3 and 4 resulting from diabetic nephropathy. The patients were randomised into 2 groups: the control group, which received conservative management for diabetic nephropathy, and the test group, which received N. sativa oil (2.5 mL once daily) in conjunction with conservative management for 12 weeks. The test group exhibited a drop in FPG, serum creatinine, blood urea and 24-hour total urinary protein levels, along with a rise in GFR, 24-hour total urinary volume and haemoglobin levels compared to the control group.^24^ Black seed products are noted for their low toxicity. The low toxicity of black seed fixed oil is evidenced by high LD50 values, key hepatic enzyme stability and organ integrity preservation.^25^ However, 2 cases of contact dermatitis have been reported following topical application.^26^ Therefore, substantial evidence suggests that black seed is a safe and reliable herbal remedy for dietary intervention in treating T2DM, enhancing glycaemic control and lipid profiles.

3.2. Fenugreek (Trigonella foenum-graecum)

Fenugreek (T. foenum-graecum) is an annual plant primarily native to India and Northern Africa. Historically, it was used for mummification in ancient Egypt and to assist with labour and delivery in ancient Rome. Additionally, it served as a tonic and a remedy for leg weakness and oedema in traditional Chinese medicine. Research has also shown that fenugreek possesses hypoglycaemic and anti-hyperlipidaemic effects.^27^ Fenugreek seeds (FS) are rich in proteins, amino acids, flavonoids, steroidal saponins, coumarin, lipids, vitamins, minerals, galactomannan fibre and alkaloids, such as trigonelline, highlighting their nutritional and therapeutic properties.^28^

Several studies have demonstrated the antidiabetic effects of fenugreek in T2DM patients. In Kassaian et al.'s clinical trial, 24 T2DM patients consumed 10 g/day of powdered FS, either mixed with yoghurt or soaked in hot water, over a period of 8 weeks. The results showed that FS soaked in hot water significantly reduced FPG, TG and very-LDL-C by 25%, 30% and 30.6%, respectively. In contrast, no significant effects were observed when FS was mixed with yoghurt.^29^ Ranade and Mudgalkar's randomised, single-blind trial investigated the antidiabetic effects of fenugreek on T2DM patients and controlled for diet, exercise and the use of OHAs or insulin. A total of 60 patients diagnosed with T2DM at least 6 months before the study (who were on OHAs and insulin) were randomised to receive either 10 g of FS soaked in hot water or no treatment. The findings revealed significant reductions in FPG levels in the fifth month for the study group, while HbA1c showed a significant reduction in the sixth month.^30^

Another randomised clinical trial involved 50 T2DM patients aged 30–65 years who were on antidiabetic drugs and receiving nutritional consultations. These patients were administered 5 g of FS powder three times daily for 8 weeks, while a control group did not receive any FS supplementation. The FS supplementation significantly reduced FPG, ALT, alkaline phosphatase, AST and SBP in the T2DM group compared to the control group.^31^

Gaddam et al.'s 3-year randomised controlled study investigated fenugreek's role in preventing T2DM in prediabetic patients aged 30–70 years.^32^ Participants consumed 5 g of FS powder twice daily before meals. By the end of the study, the FS group demonstrated a significantly lower cumulative incidence of diabetes-related indices, including reductions in FPG, postprandial plasma glucose and LDL-C, while serum insulin levels increased significantly. Interestingly, it was observed that the control group had a 4.2-times higher likelihood of developing diabetes compared to subjects in the FS group. The outcomes of diabetes in the FS group were positively associated with serum insulin levels and negatively associated with IR.^32^

Another study investigated the effect of fenugreek on the lipid profile of newly diagnosed T2DM patients.^33^ The fenugreek group received 25 g of FS twice daily for one month, while the control group was administered metformin. The results showed a significant decrease in TC levels by 13.6%, TG levels by 23.53% and LDL-C levels by 23.4% compared to baseline levels. Moreover, the FS group exhibited a significant 21.7% increase in HDL-C levels.^33^ Moosa et al.'s study showed that consuming 25 g of FS powder orally, twice daily, for 3–6 weeks led to a significant reduction in serum levels of TC, TG and LDL-C in hypercholesterolemic T2DM patients, with no significant change in serum HDL-C levels, indicating the lipid-lowering potential of FS.^34^ These studies highlight the potential role of fenugreek in lowering blood sugar and lipid levels in T2DM patients, providing a safe and effective remedy for T2DM management.

3.3. Ginger (Zingiber officinale)

Ginger is a herbal supplement that is widely used as a spice and has a long history of use in herbal medicine. Originating in Southeast Asia, ginger has been cultivated for about 2,500 years in India. Traditionally, it has been used to treat nausea, vomiting, inflammation, intestinal disturbances, diarrhoea, constipation and cold symptoms. Recent studies have also reported that ginger possesses anticoagulant and anticancer activities.^35^

Experimental research studies have shown that ginger may possess antidiabetic properties by regulating key enzymes involved in carbohydrate metabolism, including α-glucosidase, α-amylase, aldose reductase, pancreatic lipase, liver glucokinase, phosphofructokinase and pyruvate kinase. The inhibitory effects of this herb have been attributed to the compounds gingerol and shogaol found in the extract.^36^

Several randomised controlled trials (RCTs), controlled clinical studies and meta-analyses investigating the use of ginger for the treatment of hyperglycaemia in T2DM were included in this review. The meta-analyses included RCTs that evaluated the impact of ginger powder on managing hyperglycaemia in T2DM patients. Although participant eligibility criteria varied slightly among the studies, all participants had been diagnosed with T2DM for a duration of 2–10 years and did not exhibit severe diabetic complications. None of the participants had acute inflammatory diseases, smoked, consumed alcohol or were pregnant or lactating. In these RCTs, dried ginger powder was administered orally in different doses ranging from 1.6 to 3 g/day over varying durations (30–84 days). The systematic review and meta-analysis offer strong evidence supporting the effectiveness of ginger in improving glucose control, enhancing insulin sensitivity and optimising blood lipid profiles. Given its positive effects and minimal side effects, ginger may serve as a promising adjunct therapy for managing T2DM.^353738^

Various studies have demonstrated the antidiabetic properties of ginger. Khandouzi et al. conducted a study involving 41 participants (22 in the ginger group and 19 in the control group).^39^ The ginger group consisted of 5 males and 17 females, with an average age of 45.20 ± 7.64 years, while the control group included 9 males and 10 females, with an average age of 47.10 ± 8.31 years. The study found that oral administration of ginger powder at a dose of 2 g/day for 12 weeks significantly reduced FPG levels.^39^ Mozaffari-Khosravi et al. also showed that daily consumption of three 1 g capsules of ginger powder for 8 weeks was useful for patients with T2DM, as it resulted in FPG and HbA1c reduction, along with improvements in IR.^40^ Other studies have suggested that the response to ginger components is dependent on their dose concentration.^41^

Arablou et al.'s recent double-blind, placebo-controlled clinical trial included 70 T2DM patients. Participants were randomly assigned to either the ginger group or the control group, consuming 1.6 g of ginger or 1.6 g of wheat flour as a placebo daily for 12 weeks. The study found that ginger consumption significantly improved insulin sensitivity and some fractions of the lipid profile in T2DM patients.^42^ Mahluji et al. conducted a similar randomised, double-blind, placebo-controlled trial, which showed that ginger supplementation improved insulin sensitivity and various lipid profile fractions in T2DM patients. In this study, 64 patients with T2DM were assigned to either the ginger or placebo group (receiving 2g/day of each).^43^ Rahimlou et al.'s randomised controlled clinical trial involved 37 patients with metabolic syndrome. These patients were supplemented with 2 g/day of ginger powder or a placebo for 12 weeks. At the end of the treatment period, the levels of TG, FPG and IR showed significant improvement in the ginger group compared to the placebo group.^44^

In a recent study conducted by Ghoreishi et al., a randomised, double-blind, placebo-controlled clinical trial was undertaken to investigate the efficacy and safety of ginger supplements in T2DM patients with non-alcoholic fatty liver disease (NAFLD).^45^ In this study, 76 patients diagnosed with both T2DM and NAFLD were randomly assigned to 2 groups: one group received ginger powder capsules (1 g, twice daily), while the other group received placebo capsules for an intervention period of 3 months. In the group receiving ginger supplements, a significant improvement was observed in mean SBP and diastolic blood pressure. Moreover, within the ginger group, there was a notable decrease in serum insulin levels and IR, as well as a significant improvement in serum HDL-C levels.^45^

Some experimental research has shown that ginger supplements decrease oxidative stress and improve periodontal status while also increasing serum levels of antioxidant enzymes and alleviating inflammation by lowering the concentrations of TNF-α and hs-CRP in the blood. A double-blind, placebo-controlled, randomised clinical trial involving patients aged 20–60 years with T2DM who were not on insulin therapy revealed that 3 months of ginger supplementation (3 g/day) significantly improved glycaemic indices, TAC and paraoxonase-1 activity in these patients.^46474849^

The Food and Drug Administration (FDA) considers ginger safe for inclusion in the diet; however, it may cause mild side effects, including heartburn, allergic reactions, gallstones and other adverse effects. Additionally, there is conflicting evidence regarding its interaction with anticoagulant medications, such as aspirin and warfarin.^50^ To date, the FDA does not regulate its use as a supplement or medication. A comprehensive understanding of the safety of ginger requires further investigation and research.

3.4. Cinnamon (Cinnamomum cassia)

One of the most widely used herbal medicines is cinnamon (C. cassia). Cinnamon is derived from the dried inner bark of the shoots of Cinnamomum zeylanicum, which belongs to the Lauraceae family. There are two main types of cinnamon: Cassia cinnamon and Ceylon cinnamon. In addition to its medicinal purposes, cinnamon can also be used as a flavouring agent in food supplements, as well as a stimulant, antiseptic and weight-reducing agent. Cinnamon offers many health benefits and is believed to help treat various conditions, such as diabetes, hypertension, irritable bowel syndrome and the common cold.

Recently, cinnamon has been shown to be useful in blood sugar control.^51^ Research suggests that cinnamon may regulate blood sugar through various mechanisms, including the inhibition of alpha-glucosidase and alpha-amylase, reduction of aldose reductase activity, activation of PPARA and PPARG, elevation of GLP-1 levels, enhancement of pyruvate kinase activity, reduction of PEPCK activity and increased expression and translocation of GLUT transporters.^52^ Several randomised controlled clinical trials have been conducted to study the effect of cinnamon on blood glucose control in T2DM patients. Sahib's randomised placebo-controlled clinical trial evaluated the efficacy of 1 g of cinnamon per day in poorly controlled T2DM patients who were treated only with sulfonylurea. The results indicated a significant reduction in FPG levels after 12 weeks, whereas HbA1c levels exhibited a non-significant decreasing trend in the cinnamon-treated patients.^52^ Lu et al.'s randomised, double-blind clinical study involving 66 T2DM patients who were exclusively taking gliclazide found that a daily dose of 120 mg and 360 mg of cinnamon extract over 3 months resulted in a significant reduction in FPG levels and HbA1c compared to the placebo group.^53^ Additionally, Akilen et al.'s clinical trial conducted in the United Kingdom with 58 T2DM patients, all of whom had HbA1c levels exceeding 7% and were being treated with metformin and sulphonylurea, revealed that those receiving 2 g of cinnamon per day experienced a significant decrease in HbA1c levels compared to patients who received 2 g of placebo after 12 weeks of treatment.^54^ Furthermore, Mang et al. demonstrated that a daily intake of 3 g of aqueous cinnamon extract for four months significantly reduced FPG levels in T2DM patients treated with only 1 OHA, although there was no significant decrease in HbA1c levels.^55^ Sengsuk et al. conducted a clinical trial over a period of 60 days. They found that 1.5 g of cinnamon taken daily alongside antidiabetic drugs resulted in a significant reduction in both blood glucose and HbA1c levels in T2DM patients.^56^ Similarly, a 30-day clinical trial involving 1.5 g of cinnamon per day in individuals with T2DM demonstrated a significant decrease in FPG levels in the cinnamon group compared to the placebo group.^57^ Furthermore, Crawford conducted an RCT to determine the effect of 1 g of cinnamon per day on HbA1c levels in poorly controlled T2DM patients who had been using antidiabetic drugs and insulin for over 90 days. The study showed that cinnamon reduced HbA1c levels by 0.83%, compared to a reduction of 0.37% observed with antidiabetic drugs and insulin alone.^58^ In contrast, Blevins et al. demonstrated that 1 g of cinnamon per day for 3 months resulted in no significant changes in FPG, HbA1c or insulin levels in T2DM patients. This lack of effect was attributed to the heterogeneity of the United States population and specific variables (diet, ethnicity, BMI, glucose levels, cinnamon dosage and concurrent medications) that affect cinnamon responsiveness.^59^ Moreover, a randomised, placebo-controlled clinical trial reported that a daily dose of 1 g of cinnamon for 60 days did not decrease FPG or HbA1c levels among T2DM patients.^60^ Similarly, Talaei et al. found that daily supplementation of 3 g of cinnamon for 8 weeks had no significant effect on FPG, insulin or HbA1c levels in T2DM patients.^61^ However, despite its favourable effects on metabolic profiles, excessive cinnamon consumption has been documented to have adverse side effects, including liver damage, allergies, skin irritation and other complications.^6263^

3.5. Curcumin (Curcuma longa)

Curcumin is the principal active polyphenolic compound found in the turmeric plant (C. longa), which contributes to its vibrant yellow colour. It is one of the curcuminoids present in turmeric, alongside demethoxycurcumin and bisdemethoxycurcumin.^64^ Curcumin has been the focus of extensive research due to its potential pharmacological properties and medical applications, such as anti-inflammatory and antioxidant activities, wound healing, skin protection and genotoxicity protection.^65666768^ Although curcumin offers promising health benefits, its utilisation presents significant challenges related to its bioavailability. Curcumin exhibits low water solubility and permeability, resulting in reduced efficacy in aqueous solutions. Moreover, it undergoes rapid metabolism and clearance, further lowering its bioavailability.^69^

Several studies have investigated curcumin's multifaceted potential applications in managing T2DM. Panahi et al.'s randomised, double-blind, placebo-controlled trial examined the effects of curcuminoids (bioactive compounds derived from C. longa) on the lipid profiles of T2DM patients.^70^ A total of 118 T2DM patients were randomly divided into 2 groups: one group received curcuminoids (1.5 g/day), while the other group received a placebo, both for a 12-week intervention period. A significant improvement in the patient's lipid profile in the curcuminoid group was observed after the intervention, including a notable decrease in TC, non-HDL and lipoprotein (a) levels. Moreover, a significant increase in HDL-C levels was noted in the curcuminoids group. The study concludes that curcuminoid supplementation may help reduce the risk of cardiovascular diseases in T2DM patients with dyslipidaemia.^70^

Adibian et al.'s study evaluated the effects of curcumin supplementation on the lipid profile of T2DM patients by conducting a double-blind, randomised clinical trial involving 44 T2DM patients.^71^ Participants were randomly assigned to receive either 1.5 g/day of curcumin or a placebo for a treatment period of 10 weeks. The curcumin group showed a significant reduction in TG and hs-CRP serum levels, along with a notable increase in adiponectin levels. These findings suggest the potential therapeutic benefits of curcumin in reducing T2DM complications by lowering TG levels and inflammatory markers.^71^

Dastani et al.'s randomised, double-blind, placebo-controlled clinical trial aimed to evaluate the impact of nano-curcumin (nano micelles containing curcumin) on cardiovascular risk factors in T2DM patients with mild to moderate coronary artery disease (CAD). In this study, 64 T2DM patients were randomly assigned to receive either nano-curcumin (80 mg/day) or a placebo for 90 days, along with their optimal medications. After 3 months, the nano-curcumin group showed a significant reduction in the mean percentage change of hs-CRP and lipoprotein (a) levels. Furthermore, the number of patients with mild and moderate hs-CRP levels increased, while the number of patients with severe levels decreased. This study concluded that nano-curcumin might aid in preventing atherosclerosis progression and succeeding CAD in T2DM patients by reducing hs-CRP levels.^72^ A recent randomised, double-blind clinical trial by Asghari et al. also showed that supplementation with 80 mg of nano-curcumin combined with eicosapentaenoic acid, a component of omega-3 polyunsaturated fatty acids, for 12 weeks may positively affected inflammation and oxidative stress, resulting in a significant reduction in insulin levels, hs-CRP and TAC.^73^

Curcumin's potential as an antioxidant agent in eradicating free radicals and inhibiting oxidative stress has also been investigated by various research groups. Asadi et al.'s study aimed to evaluate the effect of curcumin supplementation on diabetic sensorimotor polyneuropathy (DSPN) by conducting a parallel, double-blind, randomised, placebo-controlled clinical trial involving 80 T2DM patients.^74^ Patients were randomly allocated to either the intervention group, which received 80 mg/day of nano-curcumin capsules, or the control group, which received placebo capsules, for an intervention period of 8 weeks. The nano-curcumin group demonstrated a significant reduction in HbA1c levels and a notable improvement in the total neuropathy score. The study concluded that curcumin supplementation can reduce the severity of DSPN in T2DM patients.^74^ Shafabakhsh et al.'s study showed that a daily dosage of 1 g of curcumin over 12 weeks significantly reduced MDA levels while markedly increasing serum TAC and GSH levels.^75^ Moreover, the curcumin group exhibited an upregulation of peroxisome proliferator-activated receptor gamma. Additionally, the curcumin group experienced a significant decrease in their Pittsburgh Sleep Quality Index scores. This study indicates that curcumin supplementation may mitigate oxidative damage and inflammation, as well as improve the psychological status of T2DM patients.^75^ Therefore, curcumin has shown beneficial effects on glucose, lipid and antioxidant profiles in T2DM. However, its utilisation carries significant challenges regarding its bioavailability.

Overall, the Middle Eastern herbs highlighted in this review show significant promise as complementary therapies for managing T2DM, with N. sativa emerging as the most consistently effective in demonstrating therapeutic benefits, including improvements in glycaemic control, lipid profiles and antioxidant activity. However, variations in study design and patient populations emphasise the need for further research conducted in consistent settings. Furthermore, future studies should prioritise larger, multicentre RCTs to confirm such findings, with careful attention to dosing, patient anthropometrics, compliance and potential interactions with conventional medications. Mechanistic studies are also crucial to elucidate the pharmacodynamics of these herbs, particularly their cellular and molecular effects on glycaemic control and oxidative stress. Standardising herbal preparations to enhance both safety and effectiveness is essential. Additionally, understanding long-term safety and potential side effects will support their integration into holistic diabetes care. This can be achieved through advanced extraction methods, such as chromatography, which isolates active compounds while minimising toxicity risks. Moreover, pharmacokinetic studies that measure troughs and peaks using techniques such as mass spectrometry can further support safe dosing protocols. Long-term studies are also essential for evaluating safety, efficacy, cumulative effects and potential interactions with other treatments*.* Finally, combining these herbal treatments with lifestyle modifications such as diet and exercise, may yield more practical and synergistic benefits for patients.

The variability in reported outcomes reflects the diversity of research within this field, highlighting a comprehensive view of current knowledge. This review presents a range of findings, from supportive evidence to studies with limited or inconclusive results, highlighting the multifaceted landscape of herbal interventions. While this diversity provides valuable insights, it also emphasises the need for more standardised study designs to facilitate more cohesive and unified conclusions in future research. To establish the sustained efficacy and safety of these herbal therapies or their active components for prediabetes or early diabetes, well-structured, long-term RCTs would be ideal. Such a study could include both placebo and standard therapy groups, with an interchange of treatment arms, and monitor key glycaemic and lipid markers. This design would offer valuable insights into the long-term benefits and any potential cumulative effects of herbal treatments, thereby supporting their integration into diabetes care.

4. Conclusion

In reviewing the evidence on Middle Eastern medicinal herbs for the management of T2DM, black seed (N. sativa) stands out as a herb with consistently positive outcomes in various clinical trials, making it a promising candidate for adjunct therapy in T2DM. However, the overall reliability of these findings depends on a comprehensive assessment of study design, methodology and other factors. While black seed shows promise, the broader spectrum of herbs discussed in this text should be considered as well. Fenugreek (T. foenum-graecum) has demonstrated notable hypoglycaemic and antihyperlipidemic effects, presenting a potential avenue for diabetes management. Ginger (Z. officinale) exhibits antidiabetic activity through its impact on carbohydrate metabolism enzymes, correlating with clinical trials that show positive effects on glucose control, insulin sensitivity and blood lipid profiles. Cinnamon (C. cassia) has demonstrated potential benefits in blood sugar control, although results across trials are mixed. Curcumin (Curcuma longa) has shown beneficial effects in controlling blood sugar levels and lipid profiles, along with positive antioxidant effects in patients with T2DM. Significant challenges remain before these herbs can be considered for integration into standardised clinical practice and potential regulatory approval. Importantly, with the widespread availability of information on social media and unofficial health and wellness websites, diabetic patients are increasingly inclined to independently incorporate antidiabetic herbs into their management plan. This trend necessitates a cautious, patient-centred approach, which will ensure that patients are well-informed about the potential risks and drug interactions associated with these herbs.

Authors' Contribution

Shihab Al-Makhmari: Investigation, Writing - Original Draft. Abir Al-Aufi: Investigation, Writing - Original Draft. Saleh Al-Kindi: Investigation, Writing - Original Draft. Maha Al Riyami: Investigation, Writing - Original Draft. Hussein Sakr: Writing - Original Draft, Writing - Review & Editing. Mohamed-Rachid Boulassel: Project administration, Conceptualization, Writing - Review & Editing. Khalid M. Abu Khadra: Writing - Original Draft, Writing - Review & Editing. Rahma Al-Haddabi: Validation, Writing - Review & Editing. Ammar Boudaka: Investigation, Writing - Original Draft, Project administration, Conceptualization, Writing - Review & Editing. Jumana Saleh: Investigation, Writing - Original Draft, Project administration, Conceptualization, Writing - Review & Editing.

Acknowledgements

This manuscript benefited from the implementation of the intercalated phase at the College of Medicine at Sultan Qaboos University.

Data Availability

Data are available upon reasonable request from the corresponding author.