Effect of saffron on premenstrual syndrome and dysmenorrhea: a systematic review and meta-analysis

Abstract

Background

Premenstrual syndrome (PMS) and dysmenorrhea are common symptoms in women. In this study, we investigated the effects of saffron on PMS and dysmenorrhea in women.

Methods

In this systematic review and meta-analysis, we comprehensively screened a range of databases, including PubMed, Web of Science, and Science Direct. We included randomized clinical trials investigating the effects of saffron on PMS or dysmenorrhea. Quality assessment of the identified studies was conducted using the Cochrane risk-of-bias assessment tool. Meta-analysis was performed using Comprehensive Meta-Analysis software ver. 2 based on the random effects model.

Results

Meta-analysis revealed that saffron had a significant positive effect on the symptoms of PMS in women (standardized mean difference [SMD], –0.64; 95% confidence interval [CI], –0.84 to –0.44). Furthermore, saffron was effective in reducing dysmenorrhea (SMD, –0.51; 95% CI, –1.01 to –0.01).

Conclusion

The findings of our meta-analysis indicate that saffron exerts beneficial effects on the symptoms of both PMS and dysmenorrhea in women.

Graphical Abstract

Introduction

Premenstrual syndrome (PMS) refers to a range of psychological, emotional and behavioral symptoms that occur prior to menstruation [1]. Common psychological symptoms include mood swings, irritability, and depression, whereas physical symptoms include breast tenderness, bloating, and headache [2]. PMS is a recurring condition that occurs during the luteal phase while patients remain asymptomatic between the two luteal phases [2,3]. This syndrome typically begins 1–2 weeks before menstruation, and its symptoms decrease naturally after the onset of menstruation without the need for medical intervention [1,4]. It is estimated that approximately 75% of all women experience PMS during their menstrual cycle [5]. Furthermore, PMS can affect women of all ages and backgrounds [6].

The global prevalence of PMS is 47.8%; the highest and lowest prevalence of PMS has been reported in Asia and Europe, respectively. Approximately 85% of women of reproductive age experience at least one symptom of PMS [3,7]. PMS is common in Iran, as indicated by a study conducted by Delara et al. [8]. Furthermore, 99.5% of teenage girls reported experiencing at least one symptom, 66.3% reported mild symptoms, 31.4% reported moderate symptoms, and 2.3% reported severe symptoms [7-9]. In Japan, approximately 95% of women suffer from PMS, with a prevalence of 5.3% for moderate PMS and 1.2% for premenstrual dysphoric disorder (PMDD) [9]. A Swiss study found that 10% of participants experienced PMS, whereas 3% experienced PMDD. In a previous study, conducted in the United States, the prevalence of PMS and PMDD was 8% and 5%, respectively [10].

Dysmenorrhea, also known as menstrual pain, is a discomfort that arises 1 to 2 days before menstruation, without any underlying pelvic disease. This pain typically persists for 2 to 3 days [11]. Studies indicate that 25%–50% of women experience primary dysmenorrhea [12], and that dysmenorrhea affects approximately 50% of women with regular menstrual cycles [13]. More than 10% of women experience severe symptoms that necessitate rest and disrupt their ability to perform daily tasks [14]. These women typically cannot perform their daily activities for 1 to 3 days during each menstrual cycle because of intense uterine cramps [15]. Dysmenorrhea is the most frequently reported gynecological condition among teenagers and young women [16].

Research has indicated that women with PMS or dysmenorrhea often face various challenges that significantly affect their quality of life [17]. These challenges include legal issues, suicidal ideation, reduced work productivity, social isolation, parenting difficulties, increased absenteeism, disruptions of personal and social relationships, and frequent hospital visits. PMS and dysmenorrhea can also contribute to increased susceptibility to accidents, drug addiction, financial losses, and diminished achievements [3].

Discomfort caused by PMS and dysmenorrhea often requires self-medication, and numerous prescriptions and over-the-counter products are available for pain relief [2]. Several scientifically proven therapeutic interventions can be beneficial for the clinical management of PMS and dysmenorrhea. Non-pharmacological approaches include behavioral and cognitive therapies, lifestyle and diet modifications, education, exercise, and complementary herbal medicines. Pharmacological and hormonal treatments such as gonadotropin-releasing hormone agonists and oral contraceptive pills, along with psychotropic medications such as benzodiazepines and selective serotonin reuptake inhibitors, are also utilized. However, it is important to note that each of these drug treatments carries significant side effects. These symptoms include insomnia, restlessness, nausea, sweating, muscle cramps, and tremors [3]. Approximately 80% of women who experience PMS symptoms report self-treatment with over-the-counter medications including natural health products such as herbs, vitamins, and minerals [4]. Given the chronic and long-lasting nature of PMS symptoms and dysmenorrhea, special attention should be paid to the potential side effects of pharmaceutical interventions. Therefore, the development of alternative approaches have been recommended [18]. The use of medicinal plants, such as saffron, has been shown to be effective in reducing PMS symptoms, with fewer side effects than chemical drugs [19].

Saffron (Crocus sativus L.) belongs to the Iridaceae family and has been used for centuries as a herbal medicine, spice, food coloring and flavoring agent [20]. Saffron is widely used in Iran, India, Spain, and Russia. In folk medicine, saffron has been used as an antidepressant, anticancer agent and stimulant [21]. Saffron is also recognized as an aphrodisiac, emmenagogue, gum relaxant, anti-catarrhal agent, nerve relaxant, carminative, diaphoretic, expectorant, and a stimulant of the stomach [22]. Saffron also possesses anti-inflammatory and antidepressant properties, making it potentially effective for the treatment of PMS and dysmenorrhea [18]. Experimental and clinical studies have demonstrated the efficacy of saffron in managing mild-to-moderate depression, with its antidepressant effects attributed to a serotonergic mechanism [7]. On the basis of these results and the underlying mechanisms, we hypothesized that saffron may alleviate the severity and symptoms of both PMS and dysmenorrhea.

However, contradictions exist when comparing the findings of existing original articles, and there are no unified and integrated conclusions regarding the impact of saffron on the severity of PMS and dysmenorrhea. Therefore, it is crucial to conduct a meta-analysis that combines and evaluates existing findings. Findings will help us to determine whether saffron can effectively reduce the severity of PMS and dysmenorrhea. Therefore, in the present study, we performed a comprehensive literature search and meta-analysis of the effects of saffron on PMS and dysmenorrhea.

Methods

Search strategy

This study adhered to the preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines [23]. We conducted a comprehensive search of several databases, including PubMed, Web of Science, ProQuest, Scopus, and Embase. We also used Google Scholar to broaden our literature search. To ensure that our literature review was as comprehensive as possible, we manually searched the reference lists of all identified studies to uncover additional relevant research. To minimize publication bias, we also included searches of clinical trial registries such as ClinicalTrials.gov. We also conducted searches in several clinical trial registries, including ClinicalTrials.gov, the EU Clinical Trials Register, the Australian and New Zealand Clinical Trials Registry (ANZCTR), the Cochrane Central Register of Controlled Trials (CENTRAL), the Japan Primary Registries Network (JPRN), the International Standard Randomised Controlled Trial Number (ISRCTN) registry, and the Iranian Registry of Clinical Trials (IRCT). After identifying a relevant registered trial, our initial step was to locate published articles associated with that trial. In instances where the article had not yet been published, we contacted the corresponding author via email to obtain the necessary information.

All searches were initially conducted on January 4, 2023, and subsequently updated on November 15, 2024. The searches were performed in both Farsi and English, utilizing keywords associated with ‘saffron’ and ‘premenstrual syndrome,’ along with their Persian equivalents. Consequently, MeSH keywords pertaining to the study outcome (PMS or dysmenorrhea) were amalgamated with keywords relevant to the intervention (saffron). A search strategy was applied for all studies (Appendix 1).

Inclusion and exclusion criteria

The inclusion criteria for this study were as follows: (1) studies needed to be randomized clinical trials (RCT) or quasi-experimental studies; (2) studies needed to focus on women with PMS or dysmenorrhea; (3) there were no age restrictions for the women included in this study; (4) studies needed to use saffron as an intervention, with no restrictions on the dosage or formulation of saffron, provided that it was not combined with other substances or vitamins; (5) studies needed to report quantifiable changes in the severity of PMS symptoms or dysmenorrhea as outcomes; and (6) PMS was defined and diagnosed according to standard clinical criteria, including symptom tracking and severity assessment.

The exclusion criteria were as follows: (1) studies that prescribed chemical drugs, supplements, and industrial drugs; (2) studies that used any type of intervention other than saffron; (3) studies that included saffron in combination with other substances or vitamins; (4) conference proceedings; (5) studies published in languages other than English and Farsi; and (6) studies not conducted in humans.

Study selection

The selection methodology used in this study was meticulously designed to ensure a comprehensive review of the relevant literature. Initially, an extensive search was conducted across multiple databases with no restrictions on the year of publication year. This was followed by a manual search of the reference list of the studies that were initially discovered to further widen the field of inquiry. The next phase involved a rigorous elimination process in which duplicate studies were manually removed using EndNote software. The remaining studies were subjected to a primary evaluation that involved assessing the title and introduction of each article to determine their relevance to the study. Unrelated studies were excluded from the analysis.

Subsequently, a secondary evaluation was conducted on surviving patients. This involved a comprehensive review of the full text of each article; this helped to select the final studies that were pertinent to our research. Two independent researchers executed all search processes to ensure a robust and reliable selection procedure.

Evaluating the quality of the identified studies

Quality assessment of the studies was rigorously conducted by two independent researchers using the Cochrane risk-of-bias assessment tool. Potential bias was classified into three categories based on the outcomes: low, high, or unclear.

Data extraction

Data were extracted by two independent researchers who employed a comprehensive data extraction form that included a range of details, including the author’s name, country of origin, year of publication, study design, intervention duration, sample size, target population, age of participants, daily dosage, comparison group, measured outcomes, and measurement tool used.

Statistical analysis

This study utilized a meta-analysis approach with Comprehensive Meta-Analysis software (CMA) ver. 2.0 (Biostat Inc.). Effect size was determined by computing the standardized mean difference (SMD) with a 95% confidence interval (CI). A random effects model was used, and the heterogeneity of studies was analyzed using the I² value. None of the studies reported before-after correlation or standard deviation of changes (SD_change), which was necessary for our calculations. Consequently, sensitivity measurements were performed. A meta-analysis was conducted with zero, 0.99 and 0.5 correlations separately. In all instances, the results arising from meta-analysis were consistent, leading to an estimation of the before-after correlation at 0.5. Begg’s test was performed from a funnel plot to evaluate publication bias. Sensitivity analysis was conducted to evaluate the robustness of the results by sequentially excluding each study. If the removal of a study resulted in a significant change in heterogeneity, then this the study was excluded from subsequent analysis.

Results

Study selection

During the initial search, 598 studies were identified in electronic databases and an additional 28 studies were discovered in conference proceedings, theses, dissertations, registered clinical trials, reference lists, and other sources. After the removal of 170 duplicates, 456 studies remained. After reviewing the titles and abstracts of the remaining 456 studies, 52 were found to be eligible and proceeded to a full-text review, while 28 were found to be ineligible and were discarded (Appendix 2). Finally, seven studies underwent qualitative and quantitative analyses (Figure 1).

Figure. 1.

Preferred reporting items for systematic reviews and meta-analyses (PRISMA) flow diagram for the present study.

Study characteristics

The seven RCTs included in this study consisted of five double-blind and two triple-blind trials. These studies were published between 2008 and 2021 and featured a collective sample size of 612 participants. Six studies were conducted in Iran, whereas the remaining were conducted in Australia. Furthermore, six of the studies were published in English, whereas the remaining studies were published in Persian (Table 1).

Table 1.

Characteristics of the included studies

Study (year)	Country	Design of study	Duration of treatment (no. of menstrual cycles) (X times a day)	Sample size (EG, CG)	Population (age, y)	Intervention	Daily dose of intervention (mg/d)	Comparison	Outcomes	Instrument	Reported side effects
Agha­ Hosseini et al. [27] (2008)	Iran	Double-blind RCT	(2) (2)	EG: 24	Women with PMS; EG: 35.10±7.79; CG: 33.45±7.61	Capsules of saffron (15 mg; every 12 h)	30	Placebo capsule (no precise information was provided about the content of the placebo capsules	PMS (primary outcome)	DSR	There was no significant difference in the frequency of adverse effects (3 decreased appetite, 4 increased appetite, 1 sedation, 2 nausea, 3 headache, 2 hypomania) between saffron and placebo.
				CG: 23
Khodakrami et al. [28] (2008)	Iran	Double-blind RCT	(3) (3)	EG: 57	Female students with PMS; total (20.6±3.2)	Capsules of saffron (25 mg; every 8 h)	75	The placebo was comprised of a hydroalcoholic extract and a blend of lettuce and spinach powder, all contained within a lactose base. The capsule used for the placebo group was designed to be indistinguishable from the capsules utilized in the intervention group.	Dysmenorrhea (primary outcome)	Verbal multidimensional scoring	There have been no reported side effects.
				CG: 51
Beiranvand et al. [7] (2016)	Iran	Triple-blind RCT	(2) (1)	EG: 44	Female students with PMS; EG: 21.03±2.12; CG: 20.46±1.35	Capsules of saffron (30 mg; every 24 h)	30	Placebo capsules contain 30 mg of lactose powder (30 mg/d)	PMS (primary outcome)	SPAF	There have been no reported side effects.
				CG: 44
Azimi et al. [24] (2016)	Iran	Double-blind RCT	3 (3)	EG: 60	Female students with PMS; EG: 22.7±NR; CG: 22.4±NR	Capsules of saffron (30 mg; every 8 h)	90	Placebo empty capsules	Dysmenorrhea (primary outcome)	10-point VAS	There have been no reported side effects.
				CG: 60
Nemat­Shahi et al. [18] (2020)	Iran	Quasi-experimental study	2 (1)	EG: 82	Women with PMS; EG: 36.50±10; CG: 34±5.30	Capsules of saffron (30 mg; every 24 h)	30	There was no placebo group	PMS (primary outcome)	10-point VAS	There have been no reported side effects.
				CG: 82
Rajabi et al. [25] (2020)	Iran	Double-blind RCT	2 (2)	EG: 40	Women with PMS; EG: 31.65±4.69; CG: 31.45±5.27	Capsules of saffron (15 mg; every 12 h)	30	The placebo was made of starch, which was similar in shape, color, and size to the saffron capsule.	PMS (primary outcome)	DRSP	There were gastrointestinal symptoms in 2 cases, insomnia in 1 case, and increased menorrhagia in 5 cases.
				CG: 40
Lopresti et al. [26] (2021)	Australia	Double-blind RCT	3 (2)	EG: 39	Women with PMS; EG: 49.86±0.49; CG: 48.63±0.54	Capsules of saffron (14 mg)	28	The placebo tablets had the same ingredients as the active tablet, including microcrystalline cellulose and calcium hydrogen phosphate	PMS (primary outcome)	GCS, PANAS, SF-36	There were no major adverse events reported by participants, but one withdrawal was reported due to mild adverse effects (mild digestive issues such as bloating).
				CG: 37					Dysmenorrhea (secondary outcome)

EG, experimental group; CG, control group; PMS, premenstrual syndrome; RCT, randomized controlled trial; DSR, daily symptom report; SPAF, the shortened premenstrual assessment form; NR, not reported; VAS, visual analog scale; DRSP, daily record of severity of problems; GCS, greene climacteric scale; PANAS, positive and negative affect schedule; SF-36, 36-Item Short Form Survey Health Survey.

Evaluating the quality of articles

The studies included in this analysis used various approaches to generate random sequences. Two studies used computers to generate a randomization list [24,25]. Three additional studies employed a randomized block design [7,26]. In three of the studies, the approaches used to generate random sequences were not clearly reported [18,27,28]. Allocation concealment was implemented using sealed envelopes in one study [24], whereas other studies did not provide a clear description of allocation concealment [7,18,25,27]. Seven studies provided clear information regarding the blinding process. Furthermore, none of the studies reported instances of incomplete outcome data, because the number, nature and management of incomplete outcomes were reported. Table 2 presents additional information regarding the risk of bias for the included studies.

Table 2.

Risk-of-bias assessment for included studies^a)

Study (year)	Selection bias		Patient blinding	Assessor blinding	Incomplete outcome data	Selective outcome reporting
	Random sequence generation	Allocation concealment
Agha­Hosseini et al. [27] (2008)	U	U	L	L	L	L
Khodakrami et al. [28] (2008)	U	U	L	L	L	L
Beiranvand et al. [7] (2016)	L	U	L	L	L	L
Azimi et al. [24] (2016)	L	L	L	L	L	L
Nemat­Shahi et al. [18] (2020)	U	U	L	L	L	L
Rajabi et al. [25] (2020)	L	U	L	L	L	L
Lopresti et al. [26] (2021)	L	U	L	L	L	L

L, low risk of bias; H, high risk of bias; U, unclear (uncertain risk of bias).

^a)Domains of quality assessment based on the Cochrane tools for assessing risk of bias.

The effect of saffron on PMS

A meta-analysis conducted using a random effects model indicated that saffron could improve the symptoms of PMS in women (SMD, ‒0.64; 95% CI, ‒0.84 to ‒0.44) (Figure 2). In addition, the included studies exhibited homogeneity (I²=0.01%, P=0.621).

Figure. 2.

Effect of saffron on the severity of premenstrual syndrome (PMS). SMD, standardized mean difference.

A funnel plot was used to visually investigate publication bias (Figure 3). In this regard, Begg’s test revealed no publication bias (P=0.086). Although Begg’s test did not identify significant publication bias, we utilized Duval and Tweedie’s trim-and-fill method to estimate the number of missing studies that might exist in a meta-analysis and assess the potential impact of these studies on the overall outcome. After adjusting for the missing studies, the point estimate of the overall effect size was as follows: (SMD, ‒0.59; 95% CI, ‒0.78 to ‒0.41) (Figure 4).

Figure. 3.

Funnel plot depicting publication bias in studies evaluating the effects of saffron on premenstrual syndrome. SMD, standardized mean difference.

Figure. 4.

Funnel plot depicting publication bias after applying Duval and Tweedie’s trim-and-fill method to studies evaluating the effect of saffron on premenstrual syndrome. SMD, standardized mean difference.

The robustness of the findings of this meta-analysis was ensured by performing sensitivity analysis. The results of sensitivity analysis indicated that the overall findings were not significantly affected by the exclusion of individual studies (Figure 5).

Figure. 5.

Sensitivity analysis of the effect of saffron on the severity of premenstrual syndrome (PMS). SMD, standardized mean difference.

The effect of saffron on dysmenorrhea

Based on the results of our meta-analysis, saffron could be effective in reducing dysmenorrhea (SMD, ‒0.51; 95% CI, ‒1.01 to ‒0.01) (Figure 6). However, the effect of saffron on dysmenorrhea was weaker than that of PMS alone. Furthermore, it should be noted that one of the studies included in our meta-analysis did not demonstrate any significant effect (SMD, ‒0.01; 95% CI, ‒1.54 to 0.34). In addition, we identified homogeneity among the included studies (I²=58.69%, P=0.089). Based on a funnel plot and Begg’s test, there was no evidence for publication bias (P=0.296) (Figure 7). However, after accounting for missing studies, we estimated the overall effect size (SMD, ‒0.01; 95% CI, ‒0.66 to 0.46) (Figure 8).

Figure. 6.

Effect of saffron on the severity of dysmenorrhea. SMD, standardized mean difference.

Figure. 7.

Funnel plot depicting publication bias in studies evaluating the effect of saffron on dysmenorrhea. SMD, standardized mean difference.

Figure. 8.

Funnel plot assessing publication bias after applying Duval and Tweedie’s trim-and-fill method in studies evaluating the effect of saffron on dysmenorrhea. SMD, standardized mean difference.

Discussion

The results of the present study showed that saffron reduced the severity of PMS and dysmenorrhea. All of the studies included in this meta-analysis reported a significant effect, indicating the potential for saffron as a complementary medicine for the clinical management of PMS and dysmenorrhea.

Notably, none of the studies investigating the effects of saffron on PMS and dysmenorrhea reported any significant side effects. This is a key result as it suggests that saffron could potentially be used as a safe treatment for PMS and dysmenorrhea. The absence of significant side effects in the included studies indicates that saffron may be well tolerated by individuals suffering from these conditions. However, the absence of side effects does not necessarily indicate that saffron is completely free of side effects. It is possible that the included studies did not have a sufficiently large sample size or were did not cover a sufficient time window to detect rare or long-term side effects. Furthermore, the efficacy of saffron when used to treat these conditions was not reported and should be evaluated in future studies. The discomfort associated with PMS and dysmenorrhea often leads individuals to self-medicate using readily available products to alleviate symptoms, whether prescribed by a doctor or obtained over-the-counter [2]. Considering the chronic and enduring nature of PMS and dysmenorrhea, it is crucial to consider the side effects of therapeutic interventions [6]. Owing to the potential complications and dependency associated with pharmaceutical drugs, many women prefer to address their symptoms naturally, often turning to complementary or alternative medicines. Consequently, alternative approaches are frequently used [6,29]. Various agents, including herbs, oils, minerals, and vitamins have been used to treat PMS and dysmenorrhea. Numerous nutritional supplements have also been used to mitigate symptoms of PMS. Therefore, many women with PMS and dysmenorrhea often seek relief from these natural products [6].

The mechanism by which saffron controls PMS and dysmenorrhea remains unclear. However, PMS is often accompanied by symptoms, such as depression and stress. Dysregulation of the serotonergic system has been suggested to be responsible for most PMS symptoms [30]. Depression and stress are commonly reported symptoms of PMS. Recent experimental studies and clinical trials have shown that saffron may be effective in treating mild-to-moderate depression and that its antidepressant effect is mediated through a serotonergic mechanism [30,31]. Saffron has long been used as an antidepressant [30]. In initial clinical trials, Akhondzadeh et al. [32] and Melnyk et al. [33] investigated the efficacy of saffron extract in the treatment of mild-to-moderate depression. Specifically, saffron extract inhibits the reuptake of serotonin in synapses, leading to increased levels of serotonin in the brain and enhancing its positive effects in combating depression [34]. Furthermore, studies conducted by Fukui et al. provided evidence to support the physiological and psychological effects of saffron on women, thus indicating its potential anti-stress properties [30].

Our meta-analysis revealed a high degree of statistical homogeneity among the included studies. This suggests that despite variations in study design, sample size, and geographical location, there was a consistent pattern in the reported results. This consistency strengthens confidence in the overall findings and suggests that they are robust and reliable. This indicates that our results are likely to be generalizable across different contexts and populations. However, it is important to note that statistical homogeneity does not necessarily mean that the studies were identical in all respects. However, there may still be important differences in the study populations, interventions, and outcomes that were not captured by our analysis. Therefore, although our findings provide strong evidence for the identified effect, further research is now needed to investigate the potential variations of this effect across different settings or groups.

Our study also revealed that saffron reduced the severity of dysmenorrhea. However, caution should be exercised because only a small number of studies met the necessary conditions for this stage of analysis. However, the mechanism by which saffron reduces dysmenorrhea remains unclear and requires further investigation. Primary dysmenorrhea is characterized by painful uterine cramps during menstruation in the absence of identifiable pathological lesions. This pain is believed to be associated with prostaglandins (PGs), which induce myometrial contractions, contribute to uterine ischemia and sensitize afferent nerve fibers to painful stimuli. Consequently, the main treatment for dysmenorrhea at present involves the suppression of PG synthesis [28]. Previous research conducted by Khodakrami et al. [28] suggested that the combined use of several plants, including saffron, could improve dysmenorrhea. Other studies have indicated that saffron exhibits anti-inflammatory, antispasmodic and menstrual stimulatory properties [24]. Dysmenorrhea appears to occur due to intense contractions of the uterine wall and subsequent disruption of the proper blood supply caused by vascular spasms. A study has highlighted the relaxing effects of saffron and its constituent compounds (safranal, crocin, and crostin) on blood vessels and smooth muscles [35]. Saffron has also been shown to enhance blood circulation [28]. Consequently, saffron may improve blood supply to the uterine muscles, thereby reducing spasms. However, the exact mechanism of saffron remains unclear [24].

Further research is now required to ascertain the most effective saffron combination for alleviating dysmenorrhea-related pain. Although saffron capsules have demonstrated significant efficacy in reducing dysmenorrhea pain, it is unclear whether this effect persists beyond three menstrual cycles. Therefore, further long-term studies are now needed [24]. However, the efficacy of saffron in the improvement of dysmenorrhea has yet to be fully elucidated. To date, only a limited number of studies have addressed this issue and even fewer have met the necessary conditions for inclusion in this analysis.

Interestingly, our results suggested that the effect of saffron on PMS was greater than that on dysmenorrhea. This could be due to differences in the nature of PMS and dysmenorrhea. PMS is a complex syndrome with various symptoms, and dysmenorrhea is specifically associated with menstrual pain. Thus, the mechanism of action of saffron may be more effective in addressing a broader range of PMS symptoms. PMS involves various mechanisms within the body, whereas dysmenorrhea primarily stems from pain and necessitates only pain relief.

Our study was limited by language restrictions as we only searched for studies published in Persian or English. Future research should include studies in other languages.

In conclusion, the results of this meta-analysis suggest that saffron exerts a positive effect on the symptoms of PMS in women. The studies included in our meta-analysis exhibited homogeneity and there was no evidence of publication bias. Sensitivity analysis confirmed the robustness of our findings. However, the effect of saffron on dysmenorrhea was weaker than that of PMS, with one study showing no significant effects. Nevertheless, the overall findings support the potential efficacy of saffron in reducing dysmenorrhea. Further research is now required to investigate this relationship in greater detail. These findings can inform nursing practice by considering saffron as a potential complementary therapy for managing PMS symptoms while recognizing its limitations for addressing dysmenorrhea. We recommend that nurses should educate patients about the potential benefits of saffron, monitor its use, and collaborate with other healthcare professionals to integrate it into holistic care approaches for women experiencing PMS or dysmenorrhea.

Appendix 1. Search strategy applied for each database

Databases	Search strategies	Results
PubMed	(((((((("crocus sativus L."[Title/Abstract]) OR (saffron[Title/Abstract])) OR ("Crocus sativus"[Title/Abstract])) OR (Crocus[MeSH Terms])) OR (Safranal[Title/Abstract])) OR (Crocin[Title/Abstract])) OR (Crocetin[Title/Abstract])) OR (Picrocrocin[Title/Abstract]) AND ((((((((((((((((((("premenstrual syndrome" [MeSH Terms]) OR ("premenstrual symptoms"[Title/Abstract])) OR ("Dysmenorrhea"[Title/Abstract])) OR ("menstruate"[All Fields])) OR ("menstruated"[All Fields])) OR ("menstruates"[All Fields])) OR ("menstruating"[All Fields])) OR ("Menstruation"[MeSH Terms])) OR ("Menstruation"[All Fields])) OR ("menstruations"[All Fields])) OR ("premenstrual complaints" [Title/Abstract])) OR ("Disturbances"[Title/Abstract])) OR ("menstrual disorders"[Title/Abstract])) OR ("menstrual disorder"[Title/Abstract])) OR ("pelvic pain"[Title/Abstract])) OR ("painful menstruation"[Title/Abstract])) OR ("painful period"[Title/Abstract])) OR ("period pain"[Title/Abstract])) OR ("menstrual pain"[Title/Abstract])) OR ("menstrual cramps"[Title/Abstract])) OR ("Dysmenorrhea"[MeSH Terms])	503
Scopus	((TITLE-ABS-KEY ("crocus sativus L.") OR TITLE-ABS-KEY (saffron) OR TITLE-ABS-KEY ("Crocus sativus") OR TITLE-ABS-KEY (safranal) OR TITLE-ABS-KEY (crocin) OR TITLE-ABS-KEY (crocetin) OR TITLE-ABS-KEY (picrocrocin))) AND (TITLE-ABS-KEY ("premenstrual syndrome") OR TITLE-ABS-KEY ("premenstrual symptoms") OR TITLE-ABS-KEY ("Dysmenorrhea") OR TITLE-ABS-KEY ("menstruate") OR TITLE-ABS-KEY ("menstruated") OR TITLE-ABS-KEY ("menstruates") OR TITLE-ABS-KEY ("menstruating") OR TITLE-ABS-KEY ("Menstruation") OR TITLE-ABS-KEY ("menstruations") OR TITLE-ABS-KEY ("premenstrual complaints") OR TITLE-ABS-KEY ("Disturbances") OR TITLE-ABS-KEY ("menstrual disorders") OR TITLE-ABS-KEY ("menstrual disorder") OR TITLE-ABS-KEY ("pelvic pain") OR TITLE-ABS-KEY ("painful menstruation") OR TITLE-ABS-KEY ("painful period") OR TITLE-ABS-KEY ("period pain") OR TITLE-ABS-KEY ("menstrual pain") OR TITLE-ABS-KEY ("menstrual cramps"))	122
ISI	(TS=("crocus sativus L.") OR TS=(saffron) OR TS=("Crocus sativus") OR TS=(Crocus) OR TS=(Safranal) OR TS=(Crocin) OR TS=(Crocetin) OR TS=(Picrocrocin)) AND (TS=("premenstrual syndrome") OR TS=("premenstrual symptoms") OR TS=("Dysmenorrhea") OR TS=("menstruate") OR TS=("menstruated") OR TS=("menstruates") OR TS=("menstruating") OR TS=("Menstruation") OR TS=("menstruations") OR TS=("premenstrual complaints") OR TS=("Disturbances") OR TS=("menstrual disorders") OR TS=("menstrual disorder") OR TS=("pelvic pain") OR TS=("painful menstruation") OR TS=("painful period") OR TS=("period pain") OR TS=("menstrual pain") OR TS=("menstrual cramps"))	58
Embase	("crocus sativus L.":ab,ti OR saffron:ab,ti OR "Crocus sativus":ab,ti OR Crocus:exp/mj OR Safranal:ab,ti OR Crocin:ab,ti OR Crocetin:ab,ti OR Picrocrocin:ab,ti) AND ("premenstrual syndrome":exp/mj OR "premenstrual symptoms":ab,ti OR Dysmenorrhea:ab,ti OR menstruate:ab,ti OR menstruated:ab,ti OR menstruates:ab,ti OR menstruating:ab,ti OR Menstruation:exp/mj OR Menstruation:ab,ti OR menstruations:ab,ti OR "premenstrual complaints":ab,ti OR Disturbances:ab,ti OR "menstrual disorders":ab,ti OR "menstrual disorder":ab,ti OR "pelvic pain":ab,ti OR "painful menstruation":ab,ti OR "painful period":ab,ti OR "period pain":ab,ti OR "menstrual pain":ab,ti OR "menstrual cramps":ab,ti OR Dysmenorrhea:exp/mj)	23
ProQuest	(ti("crocus sativus L.") OR ti(saffron) OR ti("Crocus sativus") OR ti(Crocus) OR ti(Safranal) OR ti(Crocin) OR ti(Crocetin) OR ti(Picrocrocin) OR ab("crocus sativus L.") OR ab(saffron) OR ab("Crocus sativus") OR ab(Crocus) OR ab(Safranal) OR ab(Crocin) OR ab(Crocetin) OR ab(Picrocrocin)) AND (ti("premenstrual syndrome") OR ti("premenstrual symptoms") OR ti("Dysmenorrhea") OR ti("menstruate") OR ti("menstruated") OR ti("menstruates") OR ti("menstruating") OR ti("Menstruation") OR ti("menstruations") OR ti("premenstrual complaints") OR ti("Disturbances") OR ti("menstrual disorders") OR ti("menstrual disorder") OR ti("pelvic pain") OR ti("painful menstruation") OR ti("painful period") OR ti("period pain") OR ti("menstrual pain") OR ti("menstrual cramps") OR ab("premenstrual syndrome") OR ab("premenstrual symptoms") OR ab("Dysmenorrhea") OR ab("menstruate") OR ab("menstruated") OR ab("menstruates") OR ab("menstruating") OR ab("Menstruation") OR ab("menstruations") OR ab("premenstrual complaints") OR ab("Disturbances") OR ab("menstrual disorders") OR ab("menstrual disorder") OR ab("pelvic pain") OR ab("painful menstruation") OR ab("painful period") OR ab("period pain") OR ab("menstrual pain") OR ab("menstrual cramps"))	9
SID	("crocus sativus L." OR saffron OR "Crocus sativus" OR Crocus OR Safranal OR Crocin OR Crocetin OR Picrocrocin) AND ("premenstrual syndrome" OR "premenstrual symptoms" OR "Dysmenorrhea" OR "menstruate" OR "menstruated" OR "menstruates" OR "menstruating" OR "Menstruation" OR "menstruations" OR "premenstrual complaints" OR "Disturbances" OR "menstrual disorders" OR "menstrual disorder" OR "pelvic pain" OR "painful menstruation" OR "painful period" OR "period pain" OR "menstrual pain" OR "menstrual cramps" OR "Dysmenorrhea")	137

Appendix 2. Excluded full-text articles (n=28)

No outcome of interest (n=11)

No intervention of interest (n=5)

No design of interest (n=12)

Reference	Reason for exclusion
1. Karpagavalli G, Rani R. A Study to assess the effect of premenstrual syndrome on quality of life among college students at Chennai. Int J Health Sci Res 2020;10:110-5.	No design of interest
2. Javadi B, Sahebkar A, Emami SA. A survey on saffron in major Islamic traditional medicine books. Iran J Basic Med Sci 2013;16:1-11.	No design of interest
3. Andersch B, Milsom I. An epidemiologic study of young women with dysmenorrhea. Am J Obstet Gynecol 1982;144:655-60.	No intervention of interest
4. Siddiqui SA, Ali Redha A, Snoeck ER, Singh S, Simal­Gandara J, Ibrahim SA, et al. Anti­depressant properties of crocin molecules in saffron. Molecules 2022;27:2076.	No design of interest
5. Shirzadegan R, Ahmadi SA, Yari F, Baharvand P, Hasanvand A. Association of premenstrual syndrome with temperaments and ethnicities; an evidence­based traditional medicine study in west of Iran. J Prev Epidemiol 2018;3:e19.	No design of interest
6. Melnyk JP, Wang S, Marcone MF. Chemical and biological properties of the world’s most expensive spice: saffron. Food Res Int 2010;43:1981-9.	No outcome of interest
7. Suaidi MT, Wong PK, Mohd Tahir NA, Chua EW. Community Pharmacists’ knowledge, attitude, and practice in providing self­care recommendations for the management of premenstrual syndrome. Medicina (Kaunas) 2020;56:181.	No intervention of interest
8. Esalatmanesh S, Biuseh M, Noorbala AA, Mostafavi SA, Rezaei F, Mesgarpour B, et al. Comparison of saffron and fluvoxamine in the treatment of mild to moderate obsessive­compulsive disorder: a double blind randomized clinical trial. Iran J Psychiatry 2017;12:154-62.	No outcome of interest
9. Talaei A, Hassanpour Moghadam M, Sajadi Tabassi SA, Mohajeri SA. Crocin, the main active saffron constituent, as an adjunctive treatment in major depressive disorder: a randomized, double­blind, placebo­controlled, pilot clinical trial. J Affect Disord 2015;174:51-6.	No outcome of interest
10. Matsumoto T, Asakura H, Hayashi T. Does lavender aromatherapy alleviate premenstrual emotional symptoms?: a randomized crossover trial. Biopsychosoc Med 2013;7:12.	No intervention of interest
11. Sadi R, Mohammad­Alizadeh­Charandabi S, Mirghafourvand M, Javadzadeh Y, Ahmadi­Bonabi A. Effect of saffron (Fan Hong Hua) on the readiness of the uterine cervix in term pregnancy: a placebo­controlled randomized trial. Iran Red Crescent Med J 2016;18:e27241.	No outcome of interest
12. Avgerinos KI, Vrysis C, Chaitidis N, Kolotsiou K, Myserlis PG, Kapogiannis D. Effects of saffron (Crocus sativus L.) on cognitive function: a systematic review of RCTs. Neurol Sci 2020;41:2747-54.	No outcome of interest
13. Bathaie SZ, Mousavi SZ. New applications and mechanisms of action of saffron and its important ingredients. Crit Rev Food Sci Nutr 2010;50:761-86.	No design of interest
14. Montazeri S. Non-pharmacological treatment of premenstrual syndrome. Afr J Midwifery Womens Health 2011;5:148-52.	No design of interest
15. Anjum N, Pal A, Tripathi YC. Phytochemistry and pharmacology of saffron, the most precious natural source of colour, flavour and medicine. SMU Med J 2015;2:335-46.	No design of interest
16. Qiao M, Zhang H, Liu H, Luo S, Wang T, Zhang J, et al. Prevalence of premenstrual syndrome and premenstrual dysphoric disorder in a population-based sample in China. Eur J Obstet Gynecol Reprod Biol 2012;162:83-6.	No design of interest
17. Fukui H, Toyoshima K, Komaki R. Psychological and neuroendocrinological effects of odor of saffron (Crocus sativus). Phytomedicine 2011;18:726-30.	No design of interest
18. Pearlstein T. Psychotropic medications and other non-hormonal treatments for premenstrual disorders. Menopause Int 2012;18:60-4.	No intervention of interest
19. Sultana A, Rahman K, Heyat MB, Sumbul, Akhtar F, Muaad AY. Role of inflammation, oxidative stress, and mitochondrial changes in premenstrual psychosomatic behavioral symptoms with anti-inflammatory, antioxidant herbs, and nutritional supplements. Oxid Med Cell Longev 2022;2022:3599246.	No intervention of interest
20. Christodoulou E, Kadoglou NP, Kostomitsopoulos N, Valsami G. Saffron: a natural product with potential pharmaceutical applications. J Pharm Pharmacol 2015;67:1634-49.	No design of interest
21. Jose Bagur M, Alonso Salinas GL, Jimenez-Monreal AM, Chaouqi S, Llorens S, Martinez-Tome M, et al. Saffron: an old medicinal plant and a potential novel functional food. Molecules 2017;23:30.	No design of interest
22. Ahmadi S, Aradmehr M, Azhari S. Saffron and childbirth; a triple blind clinical trial. QUID 2017;1(Special Issue):2846-56.	No outcome of interest
23. Asgary S, Yazdiniapour Z. Saffron and depression. Bioact Compd Health Dis 2021;4:90-2.	No outcome of interest
24. Fayzullayev JS. Saffron and its application in medicine. Eur Int J Multidiscip Res Manag Stud 2022;2:246-50.	No outcome of interest
25. Singletary K. Saffron: potential health benefits. Nutr Today 2020;55:294-303.	No design of interest
26. Modabbernia A, Akhondzadeh S. Saffron, passionflower, valerian and sage for mental health. Psychiatr Clin North Am 2013;36:85-91.	No outcome of interest
27. Gorginzadeh M, Vahdat M. Smooth muscle relaxant activity of Crocus sativus (saffron) and its constituents: possible mechanisms. Avicenna J Phytomed 2018;8:475-7.	No outcome of interest
28. Modaghegh MH, Shahabian M, Esmaeili HA, Rajbai O, Hosseinzadeh H. Safety evaluation of saffron (Crocus sativus) tablets in healthy volunteers. Phytomedicine 2008;15:1032-7.	No outcome of interest