A structured literature search was conducted up to 2024 across four major databases: PubMed, Google Scholar, ScienceDirect, and the Central Register of Controlled Trials. The objective was to identify randomized controlled trials (RCTs) that investigated the effects of Crocus sativus L. (saffron) and Melissa officinalis (lemon balm) on glycemic control.

Keywords used during the search included: “saffron”, “lemon balm”, “Crocus sativus”, “Melissa officinalis”, “diabetes”, “glycemic markers”, “HbA1c”, “insulin”, and “fasting plasma glucose”. Studies were screened for relevance based on titles, abstracts, and full texts, focusing exclusively on human clinical trials with outcomes related to glycemic parameters.

Only human clinical studies were searched in the previous databases, and animal studies were excluded. However, only relevant studies have been conducted.

While several RCTs have demonstrated the beneficial effects of saffron and Melissa officinalis on glycemic markers, the overall evidence remains inconsistent. For instance, some studies reported significant improvements in FPG and HbA1c levels, whereas others reported no changes in insulin sensitivity or glycemic control [22] [23] . These discrepancies may stem from differences in dosage, treatment duration, and study population characteristics.

For example, studies using saffron in combination with exercise have shown greater improvement, indicating a possible synergistic effect [6] [11] . However, not all studies accounted for lifestyle or dietary habits, which could have confounded the results. Additionally, some studies had small sample sizes or short follow-up periods, limiting their statistical power and generalizability. Despite these limitations, collective evidence suggests a potential role for saffron and lemon balm in managing glycemic control, although further standardization in trial design is needed [20] .

To evaluate the reliability of the included studies, several methodological aspects were assessed, including randomization, blinding, sample size, intervention duration, and control for confounding factors. Most studies were randomized and double-blind, suggesting a low risk of selection and performance bias. However, several trials had small sample sizes (n < 60), limiting the statistical power.

Moreover, only a few studies have clearly reported on dietary or lifestyle controls, which increases the risk of confounding bias. The duration of the interventions varied from 8 weeks to 6 months, with longer studies generally yielding more consistent findings. Attrition bias has seldom been addressed and compliance rates have not always been reported. Overall, the methodological quality of most studies ranged from moderate to high; however, heterogeneity in design and reporting practices limits the strength of the conclusions that can be drawn. The methodological quality and risk of bias across the included RCTs are summarized in Table 2 .

This review included 13 RCTs that investigated the effects of saffron and Melissa officinalis on glycemic markers. In particular, FBG and HbA1c levels, and insulin resistance were observed. Although the primary outcomes were comparable, these trials exhibited variations in design, duration, population, and saffron dosage.

In this study, Milajerdi et al. showed a significant difference in FBS after treatment with 15 mg of saffron (two pills per day) hydroalcoholic extract. This study measured glucose in the serum but did not assess insulin resistance or serum insulin concentration, which could ensure a more comprehensive understanding of metabolic control [19] . Aleali et al. showed a significant decrease in FPG and HbA1c levels after treatment with 15 mg of saffron (two pills per day) hydroalcoholic extracts [22] . Saffron has been shown to affect insulin concentration and reduce blood glucose levels positively. Furthermore, saffron supplementation improved glycemic indices in overweight prediabetic patients [7] , and Karimi-Nazari et al. found significant changes in FBS and HbA1c levels in overweight prediabetic patients after supplementation with 15 mg saffron for eight weeks [7] . Mobasseri et al. reported a significant decrease in FBG levels after treatment with 100 mg/day in patients with type two diabetes for eight weeks. This study could not confirm which bioactiv compounds that are responsible for the effects because the use of whole plants extracts [23] . Tajaddini et al. reported a significant reduction in FPG and insulin levels after administration of 100 mg/day saffron supplements for eight weeks in patients with type two diabetes. This study while indicates important results, does not delve into the fundamental mechanisms through which saffron extract its effects [24] . Kotanidou et al. reported no significant differences in glycemic markers. While saffron showed positive effects they were less significant compared to metformin, this study included relatively small samples size which affected the generalisation of the results [25] . Ebrahimi et al. reported no significant differences in insulin, blood glucose, or HbA1c levels. Despite some positive findings there were no statistically significant differences, short duration which may not observe long term effects of saffron [26] . Giannoulaki et al. found that after six months, the group that was treated with three sachets a day containing 28 mg of C. sativus extract diluted in 200 ml showed significant changes in HbA1c and triglycerides in patients with type one diabetes [5] . Hooshmand Moghadam et al. this study investigates the effects of saffron combined with training in obese men with type two diabetes after 12 weeks with 200 mg of saffron powder the group that takes the saffron supplement and training showed the most significant decrease in FPG, HbA1c, HOMA-IR, and insulin concentration. There are potential interaction effects from combining resistance training and aerobic training, may complicate the interpretation of the results [6] . And Rajabi et al. study that investigated the effects aerobic training with or without saffron supplements in women with type two diabetes after 12 weeks of the study the group that did aerobic training and took the saffron supplements showed significant improvement in insulin resistance and serum levels of glucose. Some mechanisms of saffron action linked to saffron supplements activating the AMP-activated protein kinase pathway, contributes to regulating glucose metabolism and insulin sensitivity [11] . Nayebi et al. showed a reduction in FBS and HbA1c levels after 500 mg twice a day of Melissa officinalis for three months in patients with type two diabetes. In this study M. O showed antioxidant effects that may help reduce oxidative stress [21] . Asadi et al. showed that after the duration of this study, there was significant variation in serum FBS, HbA1c, and TG levels and no changes in insulin level or HOMA-IRi in patients with type two diabetes. This study includes the comprehensive assessment as dietary inputs and activity were evaluated at the beginning and middle and end of the study providing an understanding of factors that could influence the outcome [20] . To my knowledge, Sadighi et al. is the only recent study to examine the effects of saffron and Melissa officinalis and showed significant differences in FBS levels in the saffron and M. officinalis groups and significant reductions in HbA1c. The M. officinalis group showed a significant decrease in insulin resistance in both the saffron and M. officinalis groups. The mechanisms of saffron contain an important component called safranal, which is known for antioxidant which may help reduce oxidative stress, M. O helps lower blood sugar levels by increasing the production of hepatic glucokinase and GLUT4 transporter both of which are essential for glucose absorption in cells [12] . Herbal products may enhance antioxidant levels and hence reduce the pathogens associated with type two diabetes [27] . More studies are required to determine the beneficial effects of MO in human and laboratory models.