Exploring the Multifunctionality of Passiflora caerulea L.: From Traditional Remedies to Modern Applications

Abstract

Medicinal plants are well-known for synthesizing a wide range of bioactive compounds used mainly in the pharmaceutical, food and cosmetic industries. The therapeutic use of Passiflora species in Europe began in the 17th century, but few studies have been carried out on Passiflora caerulea L. This is a versatile plant, an herbaceous climber, belonging to the Passifloraceae family. In the past, P. caerulea L. has been mainly used as a sedative agent, but in recent years, scientific studies have focused on exploring its functionality and pharmacological use. Phytochemical analysis has revealed several classes of phytochemical components, some of which have promising biological potential. Recent studies have confirmed the therapeutic potential of P. caerulea by demonstrating its in vivo anxiolytic and antistress effects as well as antimicrobial, antioxidant, anticonvulsant, analgesic and gastroprotective activities. While these findings have been encouraging, there has been limited research conducted on the on the phytochemical profiling, biosafety and molecular mechanisms of the biological activity of extracts from Passiflora caerulea L. This review aims to summarize and analyze the recent scientific data on biological activities of Passiflora caerulea, including phytochemical profiling, mechanisms of action of individual compounds and potential therapeutic applications.

1. Introduction

Medicinal plants have been used as an alternative therapy for treating various diseases for millennia. Over the past decades, the pharmaceutical industry has been focused on synthetic compounds for drug discovery. Nowadays, there has been a growing interest in drugs based on natural compounds. Natural remedies often present mixtures of compounds that can exhibit a wide range of biological activities. Research has shown that different phytochemicals could have synergistic interactions, which could lead to reductions in adverse effects and enhancement of therapeutic outcomes [1]. Various diseases could be treated with drugs based on plants [2,3,4,5]. In contrast, synthetic drugs, which generally contain pure substances, have gained prominence due to their low price, consistency, scalability and ability to modify chemical structures to enhance efficacy [6]. However, despite the advantage of targeting specific pathways with high precision, they often lack the diverse interactions found in natural products that can lead to a broader therapeutic effect. Recent research continues to report the presence of value and even the discovery of new molecules in medicinal plants, which has demonstrated great potential for applications in modern medicine. Medicinal plants are of great importance worldwide and hold global significance, whether used independently or as an adjunct to conventional treatments. Numerous studies have investigated their effects on human health, demonstrating their roles as antimicrobial, anticancer, antiviral, antioxidant, enzyme inhibitor, anti-aging, anti-inflammatory, antihypertensive, neuroprotective and anticoagulant agents [4,7]. It is widely believed that approximately 30% of the therapeutic pharmaceuticals on the market are derived from natural sources, primarily microorganisms and plants [5]. In certain therapeutic domains, such as oncology, the drugs derived from plants can exceed 60% [2,4]. Much research has been focused on studying the positive effects of new and unexplored medicinal plants on human health and their application in the development of new natural products [8].

The Passiflora species were introduced in Europe during the 17th century and have been greatly appreciated for their therapeutic effects [9]. For more than two centuries, these plants and their extracts have been used as a sedative for neurosis in several European countries, as well as in the United States and Canada [10]. The chemical composition of the species demonstrates the presence of various compounds, such as phenolics, cyanogenic acids, saponins, flavonoid-C-glycosides, alkaloids, etc., which are recognized as its main constituents [11]. Vitexin, luteolin and apigenin, along with other flavones, have been pointed out as the main candidates responsible for the observed biological activities of the Passiflora species and particularly for the prominent “benzodiazepine-like” anxiolytic effect [12]. Because of this specific composition, different Passiflora plants have been widely adopted by traditional medicine and applied in healing practices in numerous countries. The predominant pharmacological characteristics of plant extracts have been linked to their inhibitory effects on the central nervous system [13]. In addition, anti-inflammatory and antinociceptive properties, along with anxiogenic and anticonvulsant effects, hypoglycemic activity, sedative qualities, antibacterial efficacy, photoprotective activity, cytotoxic effects and anti-obesity potential, have been reported for some Passiflora species [2,9,14,15,16].

P. caerulea has been cultivated all over the world as an ornamental plant but also has been used in ethnopharmacology because of its nutritional benefits and medicinal properties [17]. The aerial parts, including the leaves, stems and tendrils, have been used in traditional medicine for years [18]. P. caerulea contains various compounds that contribute to its medicinal and industrial uses, including phenolics, alkaloids, glycosides, flavonoids and saponins [19]. Numerous studies indicate that bioactive phytochemicals, including flavonoids, tannins, catechins, vitamins C and E and β-carotene, play roles in preventing a wide range of diseases such as anxiety, insomnia, attention deficit hyperactivity disorder, hypertension and cancer [19,20,21]. This plant has been used in traditional remedies for various conditions related to the gastrointestinal system; the leaves are used to treat dysentery, the aerial parts act as an antispasmodic and the fruit is recognized for its ability to promote good digestion [22]. It has been found that the infusion of P. caerulea serves as a gentle antimicrobial agent in the traditional medicine practices of Argentina [17]. Moreover, recent studies have revealed the anti-inflammatory, anti-diarrheal, spasmolytic, anticonvulsant, analgesic and antioxidant properties of the extracts derived from its leaves or other aerial parts (Figure 1) [9,16,22,23,24]. The fruit extracts have been well-known for their anticonvulsant activity, enhancing cognitive function, reducing oxidative damage and activating cholinergic neurotransmission [19]. In spite of the research that has been carried out, limited research has been conducted on the various biological activities of P. caerulea, and comprehensive studies on its phytochemical profile and biological activities, as well as in vivo analysis, remain to be explored.

2. Taxonomy

The Passifloraceae family stands out as the botanical family commonly referred to as passion fruit. This family consists of approximately 20 genera and 650 species, which include vines, trees and shrubs [25]. The most common species are Passiflora edulis Sims, Passiflora edulis flavicarpa O. Deg, Passiflora ligularis Juss, Passiflora tarminiana Coppens and V. E. Barney, Passiflora incarnata L., Passiflora quadrangularis L. and Passiflora caerulea L. [26]. The genus Passiflora, specifically Passiflora caerulea L., has widely recognized species of evergreen shrub [27]. P. caerulea is mostly grown as a fruit crop or an ornamental or medicinal plant in nearly all tropical and subtropical areas globally [28]. POWO (Plants of the World Online, https://powo.science.kew.org/taxon/urn:lsid:ipni.org:names:321949-2, accessed on 2 February 2025) [29], recognizes the following scientific names as synonyms of Passiflora caerulea: P. caerulea var. angustifolia. G. Don, P. caerulea var. glauca Mast., P. caerulea var. glaucophylla Loudon and P. caerulea var. imbricate. P. caerulea has been widely used as a model in studies of physiology and plant protection, particularly concerning flower development, the resilience of its distinctive tendrils and its ability to withstand pest attacks [18]. This plant originates from the temperate areas of South American nations including Argentina, Brazil, Bolivia, Chile, Paraguay and Uruguay [17]. However, South America is considered the center of diversity, where more than 95% of the species inhabit [18]. The blue passion fruit is also cultivated in Bulgaria as an ornamental plant along the Black Sea coast [17]. While the current species distribution in the country appears to be restricted, the ongoing global climate change may catalyze its unplanned spread beyond the areas of initial introduction.

P. caerulea is a perennial woody vine that may grow to a height of 15–20 m (49–66 ft). The leaves palmate with five lobes resembling a spread hand and measure about 10–18 cm long and broad [14]. The flower exhibits a complex structure with a diameter of approximately 10 cm. It possesses five sepals and petals that are similar in appearance (Figure 2). P. caerulea is characterized by its remarkable blue–white flowers and a prominent dark purple and white corona and should be not confused with P. incarnata, which is three-lobed and has delicate purple–lavender petals and a lighter corona [14]. P. caerulea is safe for consumption when ripe, although in most cases, it has an unpleasant taste [14]. P. caerulea flourishes in well-drained soil that retains moisture throughout the growing season; however, it does not prefer severely alkaline soils, as indicated by PFAF (Plants for a Future, https://pfaf.org/user/plant.aspx?latinname=Passiflora+caerulea, accessed on 2 February 2025) [30]. While frosts may eliminate the above-ground sections of the plant, it will rejuvenate from the base in the subsequent spring. P. caerulea is frequently cultivated as a climbing plant for vertical surfaces or utilized as a ground cover alternative. Although it is capable of enduring temperatures as low as −10 °C (14 °F), it flourishes optimally in a sheltered environment oriented toward the south or west in the Northern Hemisphere. The twining branches may continuously emerge and become invasive if not removed.

3. Chemical Composition

The chemical composition of P. caerulea consists of various bioactive compounds, such as alkaloids, flavonoids, glycosides and volatiles, all of which could lead to increased therapeutic potential [21]. The compounds of the plant are remarkable subjects for pharmacological research and applications in herbal medicine. Furthermore, according to the scientific literature, the flowers and leaves of P. caerulea possess a wide variety of pharmacological activities, such as vasodilatory, antihyperglycemic, antiarrhythmic, anticonvulsant, etc. [9,16,22,23,24].

P. caerulea contains a large quantity and diversity of polyphenols. The leaves and aerial parts typically include chrysin, luteolin, quercetin, apigenin, myricetin and C-glycosylated flavonoids like orientin, isoorientin, vitexin and isovitexin, as well as alkaloids, saponins, triterpenoids, cyanogenic acids and phenolics [20,31,32]. The fruit is characterized by high content of epigallocatechin gallate, ginsenoside, naringenin, chrysoeriol, luteolin, apigenin and carbohydrates, predominantly comprising dietary fibers; pectin; and carotenoids including lycopene, α- and β-carotene, β-cryptoxanthin and zeaxanthin [12]. Some studies have reported that the environmental conditions of growth have a significant impact on the metabolic profile of P. caerulea [14,33].

Flavonoid glycosides, the primary category of flavonoids, have been found in significant quantities in the majority of the Passiflora species examined to date, serving as the principal component in several of these species [34]. It has been demonstrated that the anxiolytic activity of P. caerulea can be attributed to these compounds. Chrysin (5,7-dihydroxyflavone) has demonstrated notable activity as a ligand compound, affecting both central and peripheral benzodiazepine receptors in the nervous system, while also showcasing anticonvulsant properties [18]. C-glycosylated flavonoids are frequently found in the aerial parts of P. caerulea. Notable examples include apigenin-8-C-glucoside (vitexin), apigenin-6-C-glucoside (isovitexin), vitexin-2″-O-glucoside, vitexin-6″-O-glucoside, isovitexin-8-C-arabinoside-7-O-glucoside, apigenin-6-C-glucoside-8-C-arabinoside (schaftoside), apigenin-6,8-di-C-glucoside (vicenin-2), apigenin-6-C-rhamnoside-8-C-arabinoside, luteolin-8-C-glucoside (orientin), luteolin-6-C-glucoside (isoorientin), luteolin-6,8-di-C-glucoside (lucenin-2) and chrysin-6-C-β-D-glucoside, among others [19,22,24,35,36]. C-glycosylated flavonoids are significant chemo-markers for P. caerulea and the wider Passiflora genus parts [19,22,24]. A study conducted by Pereira et al. demonstrated that in the leaves of P. caerulea and P. incarnata, the concentrations of orientin, isoorientin and vitexin are higher than in the related species P. edulis and P. alata [37].

Harmala alkaloids, including β-carboline and indole derivatives, have been identified as trace-level secondary metabolites in numerous Passiflora species [18,38]. Harmine, harmane, harmol and several unidentified trace-level harmala alkaloids have been successfully isolated and structurally characterized in P. caerulea [16]. In 2007 research, Frye and Haustein conducted an experiment that led to the identification and quantification of harmine using HPLC in the aerial parts of the plant [21]. Scientific evidence indicates that these alkaloids are generally associated with anxiolytic and antidepressant effects in various species [18].

Research has demonstrated that the extraction of oil from P. caerulea seeds results in a yield of 29.9% [18]. This oil is primarily composed of three fatty acids: palmitic at 10.1%, oleic at 17.6% and linoleic at 63.1% [39]. Specific indexes of fats and oils have been determined to characterize these non-traditional fatty products, and certain nutritional parameters in the residual seed extraction have also been assessed [39]. In Brazil, oils from certain Passiflora species have been used for culinary and cosmetic applications [14].

Table 1 summarizes the main chemical compounds found in P. caerulea and their effects on human health.

4. Biological Activities of Passiflora caerulea L.

Scientific studies have emphasized that the extract of Passiflora caerulea L. could influence various health conditions due to its abundant phytochemical composition. The findings indicate that the plant exhibits significant biological activities, including antioxidant, anti-inflammatory, anticonvulsant, antimicrobial and several others, which are presented in Table 2.

4.1. Antioxidant Activity

The antioxidant activity of Passiflora caerulea has been pointed out as a significant biological property, essential for neutralizing reactive oxygen species, potentially reducing inflammation and cellular damage and having a positive effect against oxidative stress-related disorders. Earlier studies have shown that the phytochemical components of the plant, including the flavonoids, phenolic compounds and alkaloids, play a crucial role in its antioxidant capabilities. Many studies have underscored specific findings, further highlighting its therapeutic significance in addressing oxidative damage [19,23,25,33].

According to Sindhura and Bobby, P. caerulea leaf extract has been found to possess high antioxidant activity in five different assays [23]. Aseervatham et al. investigated this potential and observed rapid discoloration of DPPH and ABTS radicals, which they attributed to the presence of strong antioxidant reductants in passion fruit extract. The results for the P. caerulea extract have also indicated inhibitions of 80.15% and 77.85% in NO and LPO assays, respectively [19]. A study by Gerasimova et al. demonstrated that the antioxidant activity of the leaf extracts is higher than that of the pulp [17]. According to the DPPH, FRAP and CUPRAC methods, the extracts with 70% ethanol in the leaves have the highest values, while in the ABTS method, the 50% ethanol has shown the highest activity. This is consistent with the findings of Şesan, who indicated that the ethanol extract of P. caerulea leaves exhibited the highest antioxidant activity against DPPH radicals, with an IC₅₀ value of 54.01 µg/mL, comparable to the standard antioxidant BHT (IC₅₀ = 57.16 µg/mL) [33]. Similar outcomes were achieved for the antioxidant capacity through the ABTS radical scavenging assay. In a in vivo experiment by El-askary et al., the ethyl acetate fraction of P. caerulea leaves demonstrated an antioxidant potency of 71% relative to vitamin E [9].

4.2. Anti-Inflammatory Activity

Inflammation represents a complex immune response that the body activates as a protective measure against harmful stimuli, including pathogens, injuries or irritants. Throughout this process, different immune cells, such as macrophages, neutrophils and T-cells, are activated and move toward the area of injury or infection [41]. These cells produce various substances called inflammatory mediators, including cytokines, prostaglandins and reactive oxygen species (ROS), which function to remove harmful agents and initiate the healing process [42].

Several researchers have investigated the anti-inflammatory activity of P. caerulea, exploring its potential therapeutic benefits for managing conditions related to inflammation. The investigation by Sindhura and Bobby showed that the leaf extract of P. caerulea (800 mg/mL) exhibited significant inhibition of inflammatory activity—61.05 ± 1.5% in a HRBC membrane-stabilization assay. In comparison, the positive control, aspirin, demonstrated an inhibition rate of 90.41 ± 1.3% at the same concentration, underscoring the effectiveness of the leaf extract [23]. The research by Gerasimova et al. has been focused on in vitro anti-inflammatory activity by monitoring the prevention of protein denaturation [17]. In this process, the secondary and tertiary structures of proteins are destroyed, leading to decreases in their biological functions. The reported data have demonstrated that the leaf and pulp extracts of P. caerulea could be used for the prevention of albumin denaturation. It was observed that all five samples (three leaves and two pulp extracts) had better albumin protection when compared to the two known anti-inflammatory drugs diclofenac and acetylsalicylic acid. According to the analysis by El-askary et al., Passiflora leaf extracts were included in a biological study with albino mice models (each in a dose of 100 mg/kg b. wt.) to investigate their anti-inflammatory potential compared to indomethacin. The results showed that significant activities were exerted by both aqueous and ethanolic extracts, as the highest anti-inflammatory activity was observed in the ethyl acetate fraction (100 mg/kg b. wt) [9].

4.3. Antibacterial Activity

Many studies have been conducted on the antibacterial properties of medicinal plants, emphasizing their potential as a substitute for conventional treatments for bacterial infections, particularly in the context of antibiotic resistance. In recent years, there has been an increase in the interest in plant extracts demonstrating antibacterial activity [43].

Recent investigations have highlighted the antibacterial properties of P. caerulea, demonstrating its efficacy in combating a range of pathogenic bacteria. Sindhura and Bobby explored the antibacterial activity of the methanolic leaf extract of the plant (in a concentration range of 100–1000 µg/mL) against two Gram-negative bacteria—Escherichia coli (ATCC25922) and Pseudomonas aeruginosa (ATCC 27853) [23]. The results showed a higher inhibitory effect against E. coli than against P. aeruginosa. The findings of Ramaiya, Bujang and Zakaria, who investigated the antibacterial activity of other Passiflora species against Gram-negative bacteria—Pseudomonas aeruginosa (ATCC 27853), Klebsiella oxytoca (ATCC 49131), Proteus vulgaris (ATCC 49132), Salmonella enteritidis (MTCC 125239) and Escherichia coli (MTCC 423155)—also reported that the methanolic extract of the plant showed considerable inhibitory activity [44]. In contrast, in the study by Gerasimova et al., the 50% methanolic and 70% ethanolic extracts of the leaves and pulp of P. caerulea demonstrated limited antimicrobial activity (inhibition zones < 12 mm) compared to the antibiotics used [17]. No activity has been shown against Gram-positive bacteria Staphylococcus aureus ATCC 25923 and Listeria monocytogenes NBIMCC 8632 nor the Gram-negative Klebsiella pneumoniae ATCC 13883 or Proteus vulgaris ATCC 6380. In research by Badalova et al., the pulp extracts showed antifungal activity against Penicillium chrysogenum and Fusarium moniliforme. When evaluating the antimicrobial activity of fruit extracts, the strongest inhibitory activity has been shown in the ethanolic extract of Passiflora caerulea against Pseudomonas aeruginosa (ATCC 27853), and the lowest effect was against Escherichia coli (MTCC 423155) [45]. The inhibitory effect of P. caerulea against Bacillus cereus and E. coli has been investigated recently [40]. The results showed that the methanolic leaf extract and chloroform leaf extract inhibited the growth of B. cereus (MTCC-430) and E. coli (MTCC-118), respectively. Passiflora caerulea shows important antimicrobial properties, with research indicating its potential applications in fighting bacterial and fungal infections thanks to its abundant phytochemical content.

4.4. Anticancer Activity

Cancer is considered one of the most significant problems of the 21st century. Medicinal plants could be used as an anticancer remedy due to their complex biological activities. P. caerulea has been recently investigated for its anticancer properties. Research indicates that various species within the Passiflora genus exhibit cytotoxic and antitumor activities, highlighting the genus’s diverse bioactivity [46].

The results of the study by Sindhura and Bobby demonstrate the significant activity of the extract of P. caerulea against breast cancer (MCF-7) cells [23]. MTT assay results showed that the crude methanolic extract of the plant possessed considerable activity against breast cancer (MCF-7) cells. The dose-dependent cellular viability was observed, and it was found to be IC₅₀ = 50.22 µg/mL. These results necessitate deeper investigations into the pharmacological and therapeutic usefulness of extracts from P. caerulea. Ozarowski et al. compared the inhibitory activity of three Passiflora species—P. alata, P. incarnata and P. caerulea—against human acute lymphoblastic leukemia CCRF-CEM cells [24]. The data showed inhibitory effects for the P. alata and P. incarnata extracts. However, the extracts from P. caerulea did not show any activity, despite the qualitative phytochemical similarities between the profiles obtained from P. incarnata and P. caerulea. A study by Santhoshkumar et al. has explored the cytotoxic effects of P. caerulea leaf extracts combined with titanium oxide nanoparticles (TiO2NPs) on cancer cell lines such as A549, U937 and HeLa [47]. The combination showed a greater decrease in cell viability than the individual treatments, indicating a synergistic effect.

While the plant P. caerulea has shown promise in preliminary studies, further research is necessary to fully understand its anticancer potential and to identify the specific compounds responsible for its bioactivity.

4.5. Neuromodulatory Activity

Neurogenerative diseases are becoming more and more prevalent nowadays. One of the most studied properties of Passiflora species is their effect on the nervous system. Different studies have been carried out to investigate the acetylcholinesterase activity and the anticonvulsant, anxiolytic and neuromodulatory activity of Passiflora caerulea extracts [9,16,19,48].

The research conducted by Aseervatham et al. has explored the acetylcholinesterase inhibitory potential of P. caerulea, which is important in the context of neurodegenerative diseases such as Alzheimer’s disease [19]. Acetylcholinesterase is an enzyme in the brain that breaks the neurotransmitter acetylcholine, which plays a key role in cognitive function. The inhibition of this enzyme enhances the production of more acetylcholine, thus influencing memory and cognition problems [49]. Phytochemical studies have revealed that a number of the components found in Passiflora caerulea, including flavonoids, alkaloids and phenolic compounds, exhibit an AChE inhibitory effect [19,50]. In the research by Aseervatham et al., decreased levels of AChE (0.35 ± 0.86 μmol/min/mg protein) were observed in the hippocampi of pilocarpine-induced mice treated with Passiflora extract as compared to the control [19]. The same authors have shown the anticonvulsant activity of P. caerulea extract, which also influences cognitive function and contributes to oxidative damage reduction. These results are in good agreement with [9]. In their study, they reported that ethanol leaf extract (100 mg/kg b. wt) showed the highest anticonvulsant activity (63% potency relative to carbamazepine). It has been shown that different bioactive compounds, such as C-glycosyl flavones and hydroxycinnamic acid derivatives, contribute to its anticonvulsant effects.

The anxiolytic (anxiety-reducing) activity of Passiflora caerulea has been extensively studied [47,51,52]. A possible mechanism responsible for the anxiolytic effects of P. caerulea could be through the modulation of the GABAergic system. Gamma-aminobutyric acid (GABA) is a neurotransmitter that plays a crucial role in inhibiting excessive neuronal activity, leading to relaxation and reducing anxiety. It has been demonstrated that different compounds in P. caerulea could enhance GABAergic transmission by using similar mechanisms of action as benzodiazepines but with fewer side effects [53]. For example, the flavonoid chrysin has been found to bind to GABA receptors, promoting anxiolytic activity [54]. The alkaloids harmane and harmine are able to modulate neurotransmitter systems and thus express calming effects [55]. Medina et al. confirmed the anxiolytic effects of chrysin, isolated from the aerial parts of P. caerulea, through in vitro assays [48]. Additionally, Wolfman et al. showed, through experiments with mice, that chrysin enhanced both the number of entries and the duration spent in the elevated plus-maze test for anxiety, aligning with anxiolytic effects, similar to the commercial medication diazepam [56]. This finding was of high significance because the chrysin influenced the reduction of anxiety without depressing the central nervous system, as is the case of commercial benzodiazepines. Dhawan et al. have shown the aphrodisiac potential of P. caerulea. An underlying factor might be the aromatase inhibition that is responsible for the conversion of androgens to estrogens [38].

4.6. Gastroprotective Activity

In the last few years, the gastroprotective activity of Passiflora caerulea has been a subject of interest due to its potential role in treating gastrointestinal disorders. There is some evidence that the leaves could be used against dysentery, the aerial parts as an antispasmodic agent, the root and leaves as an antihelmintic and the leaves’ decoction as a vermifuge [15,22].

The ethanol extract of P. caerulea has been investigated by Anzoise et al. for its effect on colitis and inflammatory bowel disease (IBD) [22]. Colitis refers to inflammation of the colon resulting from various causes, including infections, autoimmune conditions, reduced blood supply, etc. [57]. The endothelial barrier plays a key role in inflammatory responses, and its dysfunction leads to an increase in permeability. Neutrophil proteases can break down the connections between endothelial cells, resulting in the leakage of proteins and fluids, which can lead to edema. The idea that P. caerulea extract may help reduce edema by improving vascular permeability and also reducing the ability of the colon to contract, indicating that the extract could exert a beneficial antisecretory effect in intestinal diseases, has been investigated. Phytochemical analysis of the extract demonstrated the presence of the C-glycosylated flavonoids isoorientin, vitexin, isovitexin and vicenin-2. Evidence indicates that vicenin-2 has been found to possess antispasmodic activity by inhibiting neurotropic and musculotropic activity [58]. In conclusion, it has been demonstrated that the plant exhibits anti-inflammatory, antidiarrheal, spasmolytic and antioxidant properties in preclinical models. These findings indicate that the extract and/or its active constituents may serve as a potential therapeutic alternative for IBD, thereby contributing to symptom alleviation. Additional research is necessary to clarify the specific mechanisms underlying the effects produced by the P. caerulea extract.

5. Patented Products and Applications of Passiflora caerulea Extract

Currently, there are several patents referring to a variety of products, including medicinal formulations and innovations in food and beverages, demonstrating the plant’s adaptability and promise across multiple sectors. A patented combination of three Passiflora extracts (P. incarnata, P. caerulea and P. edulis) has been found useful in the treatment of different neurological disorders such as autism, Asperger’s disorder or Rett syndrome, restoring a balance between the inhibitory GABAergic pathways and excitatory glutamatergic pathways [2]. The proprietary document claims that the supplementation of the extracts reduced the irritability score in 25% of patients after 10 weeks of treatment. That study indicates that when the same extract was given to people with pervasive developmental disorders between the ages of 5 and 8, the people had improved states of humor, self-control and empathy, better sleep patterns, reduced aggressiveness, better attention, reduced aggressiveness, improved attention and eye contact and reduced hyperactivity. A combination of Melissa officinalis L. and P. caerulea was standardized in capsules and was named “MELIPASS^®” (Trade Mark of KNOP Laboratorios Ltd.a., Chile, South Amercia). It was found that those two extracts exhibited a diminution in chronic stress [53]. Furthermore, Keck et al. observed a reduction in the number of benzodiazepine prescriptions for hospitalized psychiatric patients following the administration of commercial phytotherapeutic tablets (Ze 185, Relaxane^®) derived from Petasites hybridus (L.) Gaertn., B. Mey. and Scherb (“butterbur”), Valeriana officinalis L. (“valerian”), M. officinalis (“lemon balm”) and P. incarnata, all of which contain isovitexin, a flavone also found in P. caerulea as one of the primary components [59]. Table 3 provides an overview of a few examples of the patented products originating from Passiflora caerulea L.

6. Toxicity of P. caerulea L.

There is limited information about the toxicity of Passiflora caerulea in the scientific literature. Nevertheless, concerns exist about the presence of cyanogenic glycosides in P. caerulea, which could pose a risk of toxicity. Cytotoxicity has been connected with oxidative stress, increased production of reactive oxygen species (ROS) and decreased levels of glutathione. Recently, El-askary, Younis and Abou-Hussein investigated the toxicity of Passiflora caerulea aqueous/ethanolic leaf extracts on albino mice and reported an LD₅₀ > 5.0 g/kg body weight [9]. Other research by Şesan has revealed that the extract of P. caerulea leaves does not inhibit fibroblast growth in vitro (NCTC L929 cell line) at concentrations of up to 150 μg/mL after 48 h of assessment [14]. Additionally, no morphological alterations or changes in cell density have been observed under microscopy. Contrarily, at concentrations higher than 250 µg/mL, the plant extract has become cytotoxic. In another study, Sindhura and Bobby and Ożarowski et al. demonstrated that the Passiflora extract showed toxicity in a dose-dependent manner. However, there is no systematic toxicological assessment of the plant and its extracts, and future research is needed to evaluate the safety of its consumption [23,65].

7. Conclusions

Passiflora caerulea shows considerable promise in numerous medicinal uses thanks to its abundant phytochemical composition and wide-ranging pharmacological characteristics. Recent studies have underscored its efficacy in addressing anxiety, insomnia and inflammation while also showcasing potential antioxidant, analgesic and antimicrobial properties. Even with these developments, the exact mechanisms of action, optimal dosages and long-term safety profiles still need more exploration. Future research should emphasize standardized clinical trials, assessments of bioavailability and the investigation of innovative therapeutic applications, especially in the areas of neuroprotection and immunomodulation. P. caerulea’s multifunctionality makes it a promising option for integrative medicine, potentially offering substantial contributions to both traditional and contemporary therapeutic methods.

Author Contributions

Conceptualization, A.G., V.G. and P.H.-H.; methodology, A.G.; resources, V.G.; data curation, A.G.; writing—original draft preparation, A.G.; writing—review and editing, A.G., V.G. and P.H.-H.; visualization, A.G.; supervision, V.G.; project administration, A.G. and P.H.-H.; funding acquisition, A.G. and P.H.-H. All authors have read and agreed to the published version of the manuscript.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

The following abbreviations are used in this manuscript:

DPPH	2,2-Diphenyl-1-picrylhydrazyl
ABTS	2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid)
NO	Nitric Oxide
LPO	Lipid Peroxidation
FRAP	Ferric Reducing Antioxidant Power
CUPRAC	Cupric Ion Reducing Antioxidant Capacity
IC50	Half-Maximal Inhibitory Concentration
ROS	Reactive oxygen species
BHT	Butylated Hydroxytoluene
MTT	3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide
AChE	Acetylcholinesterase
GABA	Gamma-aminobutyric acid
IBD	Inflammatory bowel disease
TiO2NPs	Titanium dioxide nanoparticles
LD50	Lethal dose, 50%

Footnotes

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Figures and Tables

Figure 1. Biological activities of Passiflora caerulea L.

Figure 2. Passiflora caerulea L.

Table 1

Chemical compounds found in P. caerulea L. and their effects on human health.

Chemical Class/Chemical Compound	Main Bioactive Properties	References
Flavonoids
Quercetin	Antiallergic, anticancer, antiviral, neuroprotective	[25]
Kaempferol	Antiallergic, anticancer, antiviral, neuroprotective	[25]
Luteolin	Antiallergic, anticancer, antiviral, neuroprotective	[25]
Myricetin	Antioxidant, anti-inflammatory, antimicrobial	[24]
Naringenin	Antioxidant, anti-inflammatory, neuroprotective	[24]
Chrysin	Anti-inflammatory, antimicrobial, immune-modulating	[24]
Orientin	Antioxidant and anti-inflammatory	[24]
Isoorientin	Antioxidant and anti-inflammatory	[24]
Vitexin	Antioxidant, anti-inflammatory, antimicrobial	[24]
Isovitexin	Anti-anxiety, antioxidant, anti-inflammatory	[24]
Amentoflavone	Antioxidant, anti-inflammatory, potential neuroprotective	[19]
Epicatechin	Adaptogenic, anti-inflammatory, neuroprotective, antioxidant	[19]
Flavonoid Glycosides
Luteolin-3-glucoside	Anticancer	[25]
Chrysoeriol 8-C-glucoside	Antioxidant, anti-inflammatory, neuroprotective	[35]
Apigenin-6,8-di-C-β-D-glucopyranoside	Antioxidant, anti-inflammatory, antimicrobial	[35]
Glucosyl Flavonoid	Sedative and antioxidant	[24]
7-O-Methyl-Isorhamnetin-3-O-Glucoside	Antioxidant and anti-inflammatory	[19]
Chrysoeriol 8-C-glucoside	Antioxidant and anti-inflammatory	[19]
Hesperidin (Hesperetin 7-O-rutinoside)	Anti-anxiety, antioxidant, neuroprotective.	[19]
Triterpenoids		[19]
Ginsenoside	Antioxidant, anti-inflammatory	[19]
Phenolic Acids		[19]
Chlorogenic Acid	Antioxidant, anti-inflammatory, antimicrobial.	[19]
Caffeic Acid	Antioxidant	[19]
Protocatechuic Acid	Antioxidant and anti-inflammatory	[19]
Glycosides
Saponins	Antiallergic, anticancer, antiviral, neuroprotective	[35]
Cyanogenic Acids	Anxiolytic, antioxidant, anticancer	[24]

Table 2

Biological activities of Passiflora caerulea L.

Bioactivity	Source (Type) of Extract	Method of Obtention	Experimental Method	Results	References
Antioxidant activity	100 mg/mL methanolic leaf extract	DPPH (% of inhibition)	In vitro	90.68 ± 2.11%	[23]
		ABTS (% of inhibition)		53.11 ± 2.66%
		Reducing power (% of reduction)		72.23 ± 1.12%
		NO (% of inhibition)		69.0 ± 3.97%
		Ferric Reducing Power assay (% of inhibition)		5.18 ± 2.2%
	Fruitextract	ABTS (IC50)	In vivo	IC50 = 38.13 μg/mL	[19]
		DPPH (IC50)		IC50 = 34.72 μg/mL
	100 μg/mL extract	NO (% of inhibition)		80.15%
		LPO (% of inhibition)		77.85%
	P. caerulea leaves(50% ethanolic extract)	(mM TE g−1)	In vitro	(mM TE g−1)	[17]
		DPPH		97.89 ± 5.45
		ABTS		105.46 ± 3.60
		FRAP		44.67 ± 2.50
		CUPRAC		164.37± 8.28
	P. caerulea pulp (50% ethanolic extract)	DPPH		29.74 ± 0.57
		ABTS		27.76 ± 0.80
		FRAP		14.34 ± 0.06
		CUPRAC		83.35 ± 0.09
	P. caerulea leaves (70% ethanolic extract)	DPPH (IC50)	In vitro	IC50 = 54.01 µg/mL	[9]
		ABTS (µmol/g dw)		79.77 ± 6.76 µmol/g dw
	Diabetic + ethyl acetate fraction of P. caerulea leaves	Determination of glutathione in the blood of alloxan-induced diabetic rats (%)	In vivo	71% potency relative to vitamin E	[23]
Anti-inflammatory activity	800 mg/mL P. caerulea methanolic leaf extract	Antihaemolytic activity	In vitro	61.05 ± 1.5%	[23]
	50% ethanol P. caerulea leaf extract (1.5 mg/mL);70% ethanol leaf extract (1.9 mg mL−1);methanol leaf extract;50% ethanol pulp extract; 70% ethanol pulp extract	Anti-denaturation assay (% of inhibition denaturation)	In vitro	50% ethanol P. caerulea leaf extract—highest inhibition	[17]
	Ethyl acetate fraction(100 mg/kg b. wt)	Hind-paw edema method	In vivo	90% potency relative to indomethacin	[9]
Antibacterial activity against Escherichia coli Pseudomonas aeruginosa	100–1000 µg/mL methanolic leaf extract	Agar diffusion assay	In vitro	1000 µg/mL—highest inhibition	[23]
	10 mg/mL leaf extract(50% ethanolic extract)	Agar diffusion assay	In vitro	Inhibition zone, mm	[17]
Bacillus subtilis				10.5 ± 0.71
Bacillus cereus				10.0 ± 0.00
Enterococcus faecalis				10.0 ± 0.00
Salmonella enteritidis				9.5 ± 0.71
Escherichia. coli				9.0 ± 0.00
Pseudomonas aeruginosa				9.0 ± 0.00
	Methanolic leaf callus extracts of P. caerulea (1 mg/disk)	Agar diffusion method	In vitro	Zone of inhibition, mm	[40]
Bacillus cereus				8.00
Salmonella typhi				–
Pseudomonas aruginosa				7.00
Streptococcus epidermis				–
E. coli				7.00
Anti-breast cancer activity	Methanolic leaf extract	MTT assay	In vitro	IC50 = 50.22 µg/mL	[23]
Acetylcholinesterase activity	Fruit extracts	Method of Ellmam	In vivo	Enzyme activity—0.35 ± 0.86 μmol/min/mg protein	[19]
Anticonvulsant activity	P. caerulea fruits100 and 200 mg/kg	–	In vivo	Able to halt the development and precipitation of seizures	[19]
	Ethanol leaf extract (100 mg/kg b. wt)	Frequency pulse shock	In vivo	63% potency relative to carbamazepine	[9]
Analgesic activity	Ethyl acetate fraction of leaf extract (100 mg/kg b. wt)	Writhing test induced by acetic acid	In vivo	49.1% potency relative to indomethacin	[9]
Antipyretic activity	Ethanol leaf extract (100 mg/kg b. wt)	-	In vivo	90% potency relative to paracetamol	[9]
Spasmolytic activity	Passiflora leaf extract	-	In vivo	76.25% potency relative to control	[22]

Abbreviations: DPPH—2,2-Diphenyl-1-picrylhydrazyl; ABTS—2,2′-Azino-bis (3-ethylbenzothiazoline-6-sulfonic acid); NO—Nitric Oxide; LPO—Lipid Peroxidation; FRAP—Ferric Reducing Antioxidant Power; CUPRAC—Cupric Ion Reducing Antioxidant Capacity; IC₅₀—Half-Maximal Inhibitory Concentration; mg/kg b. wt—Milligrams per Kilogram Body Weight.

Table 3

Patented products and applications of P. caerulea L.

Patent/Medicine	Description	References
Beverages
Passiflora caerulea and Honey Peach Complex Juice	This beverage features a blend of Passiflora caerulea juice, honey peach juice, honey and water. The use of enzymatic treatment effectively preserved the unique flavors of each fruit, resulting in a natural and lasting taste experience.	[60]
Sugar-Free Passiflora caerulea Tomato Sauce	A particular tomato sauce is created by blending Passiflora caerulea with tomatoes without adding any sugars.	[61]
2. Food Products
Preserved Passiflora caerulea	A technique for producing preserved products from Passiflora caerulea.	[62]
3. Medicinal and Nutraceutical Applications
Composition for Sleep Disorders	A formulation designed to prevent, alleviate or treat sleep disorders.	[63]
Composition for Neurological Disorders	A formulation designed to alleviate, prevent or treat neurological disorders such as hypnosis and forgetfulness.	[64]
Melipass® Capsules	Phytotherapeutic capsules that combine two herbal extracts: Melissa officinalis and Passiflora caerulea.	[53]

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