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   Oct 07

Passion Flower (Passiflora incarnata) – Botany, Therapeutic Uses, Constituents, Pharmaco, Adverse Effects

Unlike the many herbs that originated in Asia and the Mediterranean region, passion flower is native to the American continent. Written accounts of its use date only from the fourteenth century with the arrival of the Spanish in the Americas. As it was obvious to the Europeans that use of passion flower was a common custom among the locals, it is likely this plant had been consumed for centuries as a nutrient and herbal remedy. Today, passion flower is grown throughout the world.

The name passion flower was not bestowed on this plant because it was thought to enhance sexual attractiveness or performance. Rather, to the Spanish missionaries the components of the complex flower symbolized items associated with the passion of Christ. For example, the radial filaments represented the crown of thorns, the tendrils Roman whips, and the pointed leaf the tip of a lance.

There are hundreds of species of passion flower and a similar number of hybrids. Two that are commonly used as herbal supplements are Passiflora incarnata, which is native to the southern United States, and Passiflora edulis, which originated in portions of South America. In Latin, incarnata means flesh-colored, describing the flower petals of this species, and edulis means edible, which refers to the fruit produced by the plant. Some of the common names for Passiflora incarnata are maypop, purple passion flower, and wild apricot. Passiflora edulis is better known as passion fruit. In Brazil, members of this genus are referred to collectively as maracuja.

Native Americans consumed passion fruit for its nutritional value and calming properties. By the eighteenth century European writers were describing the plant as a treatment for epilepsy and insomnia. Today, the herb is employed primarily to relieve anxiety and to facilitate sleep. As these uses imply a pharmacological effect on the central nervous system, attempts have been made to identify the chemical constituents of passion flower responsible for them. A review of the scientific literature suggests no consensus on the existence or identity of a pharmacologically active compound, and no definitive clinical data proving that passion flower extract is a reliable and effective anxiolytic and hypnotic.

Passiflora incarnata is a member of the passion flower family, Passifloraceae. There are more than 500 species of passiflora scattered throughout the world. Insects and hummingbirds are responsible for pollination. Found in warm climates, passion flower thrives in South America and the West Indies. Nine species are native to North America, with Passiflora incarnata, or passion flower, and Passiflora lutea, or yellow passion flower, being among the most common. Passiflora incarnata is a perennial climbing vine that grows up to 24 feet in height. The flowers are produced in abundance from May to October. The fruit, which is referred to as maypop or passion fruit, is three inches long and ellipsoidal, much like a plum. The flesh is considered pleasant tasting and cooling. Passiflora lutea grows to about half the height of incarnata. The flowers of Passiflora lutea are light yellow, and its purple fruit is about one inch long. Passiflora edulis, the native South American species, is between 15 and 20 feet in height and produces a three-inch ovoid fruit that can vary in color between yellow and deep purple.

Some 16 species of passiflora yield edible fruit. The flowers of most species are large and sweet smelling. The plants are grown for their floral appearance and for the fruit. It is believed that Passiflora incarnata was cultivated by Native Americans for both the fruit and as an herbal remedy. Passion flower grows wild in the southern half of the United States, reaching as far north as southern Kansas and Missouri, and east from the Rocky Mountains to the Atlantic coast.

The Passiflora incarnata herb is listed in the European Pharmacopoeia. It is recommended for the treatment of anxiety and insomnia. In the United States, passion flower herbal tea is employed for the same purposes.

Therapeutic Uses
Passion flower extract is available commercially as a dry powder, or in a capsule or liquid formulation. The herb was used by Native Americans as a systemic tonic, and to treat swellings and sore eyes. Today, Passiflora incarnata extract is approved in Germany as a treatment for nervous restlessness, mild insomnia, and gastrointestinal complaints of nervous origin. While this product is consumed primarily for relieving anxiety and improving sleep, laboratory animal research suggests other possible uses. These include treatment for opiate withdrawal, neuralgia, cardiac arrhythmias, and inflammatory conditions. Extracts derived from various species of passion flower have been reported as treatments for pain, asthma, diarrhea, dysmenorrhea, burns, and hemorrhoids. This extract is also purported to be useful for lowering blood pressure, alleviating headache, and treating diabetes and skin conditions.

Much of the data on the therapeutic properties of passion flower are difficult to interpret as different plant species are employed in these studies. Further complicating matters is that the portion of the plant used to produce the extract may differ among studies, as may the route of administration and dosage. As the chemical constituents in a passion flower extract differ, both qualitatively and quantitatively, among species, it is not surprising that reported biological responses to the extract vary among investigators. Still, it is unlikely that any single plant genus, regardless of the number of species and variety of chemicals produced, would display such a wide range of beneficial effects. To define more precisely the clinical utility of passion flower it is necessary to identify precisely the species being studied and, ideally, the chemical compounds in the extract responsible for any response.

Passion flower extract is derived from the aerial portion of the plant, with or without the flowers. The herb was listed in the United States National Formulary from 1916 to 1936. The National Formulary provided methods and criteria for pharmacists and others for standardizing herbal products in use at that time. Dried leaves, with portions of the stem, are the main plant constituents used for making the extract. Today, standard preparations of the herb contain up to 2.5% flavonoids, most as glucosyl derivatives. The major flavonoids present in these preparations are chrysin, vitexin, isovitexin, schaftoside, isoschaftoside, orientin, isoorientin, homoorientin, apigenin, and swertisin.

Alkaloids are another chemical class represented in passion flower extracts. Individual agents include harmane, harmol, harmaline, and harmalol.6 Maltol, a flavor enhancer found in many plants, is also produced by passion flower. Numerous other chemicals and chemical classes have been identified in passion flower extracts. Undoubtedly there are scores of other, as yet unidentified, chemicals in these products. The flavonoids and alkaloids in all species of passion flower are found in other plants. As the concentrations of the alkaloids in passion flower are much lower than for the flavonoids, the latter are thought to be most responsible for the pharmacological responses associated with this plant.

There is considerable variation in the concentrations of the flavonoids and other compounds among passion flower species and in different portions of the plant.10 The leaf extracts display the most anxiolytic activity in mice, followed by stem and flower extracts, with root extracts being incapable of inducing this response.

Genetic diversity among the species is a major determinant of the chemicals produced by the plant. For example, two distinct chemotypes found in passion flowers are cultivated in Australia. The most common of this duo produces an extract with high concentrations of isovitexin, schaftoside, and isoschaftoside, while the other has high levels of swertisin and low levels of schaftoside and isoschaftoside. Thus, plants appearing identical to the naked eye, and even upon microscopic examination, can yield different products. Furthermore, as with all flora, differences in the chemical composition of an extract, even from the same cultivar, occur with variations in the age of the plant, the time of harvest, and local growing conditions. The solvent used and the method of extraction are also important variables in determining which plant constituents and their concentrations appear in the final product. This might explain why in some, but not other, animal studies it was found that an aqueous extract was more sedating, while ethanol and methanol extracts were more anxiolytic. Others found that a chloroform extract yielded the most active anxiolytic activity when tested in mice, while an ethanol extract was more effective than an aqueous solution in suppressing free radicals and preventing tissue damage. Because of differences in source materials, and the resultant variability among extracts, it is virtually impossible for investigators to replicate precisely the work of others. It also poses a challenge for the consumer with regard to the consistency of commercial products.

Chrysin and vitexin are two passion flower flavonoids suspected of being pharmacologically active. Others receiving attention are orientin, apigenin, and swertismarin. Samples of these purified substances were examined in vivo and in vitro to assess the likelihood that one, or perhaps a combination of them, is responsible for the reported therapeutic effects of passion flower. Such data are the most reliable and reproducible as they are generated using a single, chemically identified, substance. The majority of published studies, however, employ a passion flower extract, limiting interpretation of the findings. Given the complex taxonomy of this genus, morphological similarities among the numerous species, the variety of chemicals present in the plant extract, and the variations in the chemical content of the plant and extract in genetics, in extraction method, and other factors, the literature on the pharmacokinetic and pharmacodynamic properties of passion flower is often contradictory, confusing, and inconclusive. If passion flower extract is affecting central nervous system function, the current evidence is unpersuasive that the chemical constituent responsible for its action has been identified.

A great deal of in vitro data suggest that plant flavonoids in general can influence biochemical responses in a variety of tissues and organs, including the brain. However, only a small fraction of this compound class has been subjected to detailed pharmacokinetic studies.

There has been interest for some time in chrysin pharmacokinetics because of its purported effects on hormone metabolism and brain function. The intestinal absorption of chrysin is limited due to metabolic transformation in the gastrointestinal system and the presence of an efficient transport system that prevents significant quantities from entering the bloodstream. Such findings raise doubts about chrysin being responsible for any of the pharmacological effects of passion flower extract.

In other studies, four passion flower flavonoids, isovitexin, vitexin, orientin, and homoorientin, were administered orally to rats to examine their metabolism and excretion.16 As the majority of the administered dose of these agents was found in the feces, it appears these flavonoids are not readily absorbed into the systemic circulation. When given alone to rats, the maximum blood levels of vitexin were attained in less than an hour following oral administration, and its serum half-life was approximately two and a half hours. The liver and kidney were the organs with the highest concentrations of this compound. Notably, none was found in the brain. As most of the administered dose of vitexin was recovered in the feces, it was concluded that its absorption is limited following this route of administration. Indeed, it is estimated that only 3% to 4% of an orally administered dose of vitexin makes its way from the gastrointestinal system into the bloodstream. Thus, the bulk of the ingested agent never exits the digestive tract. Of the small fraction that does reach the circulation, the majority is rapidly metabolized in the liver. These findings, especially the absence from the brain, make it appear unlikely that vitexin is responsible for any of the central nervous system effects of passion flower.

With regard to apigenin, studies in rats indicate it is slowly absorbed following oral administration. However, its appearance in blood is limited by the fact that it is metabolized by intestinal bacteria and, once absorbed, rapidly metabolized by the liver. A study with human volunteers revealed that small quantities of apigenin appear in blood following the consumption of parsley. No information is available on whether apigenin appears in the brain when it is consumed orally and, if so, what the concentrations are when it is taken in this manner. Inasmuch as its absorption from the gastrointestinal system is limited, and a significant fraction is metabolized before it can be absorbed, there is little likelihood that the brain concentrations of apigenin are sufficient to induce changes in central nervous system function.

Although luteolin appeared in rat and human blood after it was taken orally, a significant portion was metabolized in the intestine and liver, limiting the amount available for mediating pharmacological effects. While in rats it appears luteolin absorption occurs primarily by passive diffusion, up to one-third of the quantity ingested is excreted in the feces. It is evident, therefore, that only a limited amount of luteolin finds its way into the bloodstream even when it is administered in solvents that would be expected to facilitate its absorption. It is likely that the passage of luteolin from the human gastrointestinal system into blood would be much less than that reported in these laboratory animal studies as the extract formulation used clinically would not be as optimal for its absorption.

As for orientin, very little, if any, of this compound was found in rat brain following its intravenous administration. This indicates that orientin is not sufficiently lipid soluble to cross into the brain even if significant quantities are present in blood. Such a finding suggests that, like the other passion flower flavonoids examined, orientin is not a good candidate as the constituent responsible for central nervous system effects.

Laboratory studies demonstrate that passion flower extract, and some of the individual flavonoids contained in this product, have the potential to influence the response to other drugs. In vitro experiments revealed that this extract can interfere with a transport system that restricts the absorption of drugs used to treat breast cancer. If such an interaction occurs in humans, co-administration of the extract with these chemotherapeutics could enhance their effectiveness. Conversely, these data also indicate that by affecting this efflux transporter system, the passion flower extract could facilitate the absorption of toxic agents that would normally be excreted before gaining entry into the systemic circulation.

There are numerous reports on the ability of chrysin, apigenin, and luteolin to affect the activity of drug metabolizing enzymes. Both enhancement and inhibition of enzyme activity have been reported, depending on the type of in vitro analysis performed and the particular enzyme examined. As such studies are generally conducted in vitro, their relevance to what occurs in humans consuming this supplement is unknown.

These pharmacokinetic data indicate that passion flower flavonoids penetrate poorly into the bloodstream following oral administration. For this reason alone, they are not good candidates as the chemical constituents responsible for the pharmacological effects of passion flower extract. The finding that some of these flavonoids can influence the transport of certain drugs and toxic agents into and out of the gastrointestinal system could be of clinical significance since this does not necessarily require absorption into the systemic circulation. If consumed in sufficient quantities, passion flower extract could very well modify the absorption of other substances as the herb travels down the gastrointestinal tract.

The fact that passion flower extract affects central nervous system function has been demonstrated in a host of in vivo laboratory animal studies. In particular, a number of investigators have reported that administration of the extract to rats or mice induces antianxiety, or anxiolytic, and sedative effects. What complicates these findings is that extracts from different plant species are used for these studies, different solvents are employed for the extraction procedure, and various doses are tested using different routes of administration. With regard to plant species, extracts from Passiflora incarnata, edulis, alta, and quadrangularis are just some of those examined. Solvents used to prepare these extracts include water, alcohol, butanol, petroleum ether, and chloroform. The doses of extract administered ranged from less than 0.4 to up to 600 mg/kg, administered either orally or by intraperitoneal injection. While some investigators report an anxiolytic response to an aqueous extract, others found that an aqueous fraction is inactive in this regard. There are also marked differences in the anxiolytic response to extracts prepared from butanol and chloroform. Experiments with isolated flavonoids indicated that, when administered alone, both chrysin and apigenin display anxiolytic activity in rats and mice. In these studies, chrysin was also shown to cause sedation and to induce skeletal muscle relaxation. Others, however, suggest that because the aqueous passion flower extract contains only small quantities of flavonoids, this compound class, which would include chrysin and apigenin, could not possibly be responsible for the antianxiety and sedative responses to this herb. When studied as purified substances, neither the alkaloid harmane, nor maltol, induce any behavioral effects in laboratory animals.

While the vast majority of these studies suggest that passion flower extract displays anxiolytic and sedative properties in rodents, there is no consensus on the optimal extraction procedure and dose needed to induce robust and consistent responses in these subjects. This raises questions about the meaning of these results in terms of their relevance to human use, and their value for identifying the pharmacologically active substance. If a single compound is responsible for the pharmacological effects, it should be most evident when it is extracted in a particular solvent. As this is not the case, either various constituents are present in passion flower that are capable of directly modifying brain function or the behavioral changes noted in the laboratory result from nonspecific effects of extract constituents on behavior.

The therapeutic utility of passion flower extract has also been suggested by placebo-controlled clinical trials. Volunteers who consumed one cup of passion flower tea each day for a week reported a better quality of sleep than a control group that did not receive the beverage. Given the large doses that normally must be administered to laboratory animals to evoke a behavioral effect, and the pharmacokinetic properties of the passion flower constituents thought to be responsible for its central nervous system actions, it is questionable whether the small quantities consumed in a cup of tea would be sufficient to have any objective effect on sleep.

Clinical trials have also suggested that passion flower extract is an effective treatment for generalized anxiety disorder, supporting the idea that this herb has anxiolytic effects. A similar conclusion was drawn from other studies comparing the antianxiety response to passion flower to that associated with oxazepam, an established anxiolytic drug. Moreover, it was reported that preoperative patients who took a passion flower product had lower anxiety scores than preoperative patients not given the herbal supplement.

The clinical data on passion flower have been used to justify its listing as one of 9 plants out of 1,000 examined that displays evidence of inducing a therapeutic effect. Nonetheless, passion flower clinical trials conducted thus far are limited in number and have yet to be replicated with larger patient populations and rigorous measures of efficacy. While the animal and clinical experiments tend to support the use of passion flower extract as a calming agent, further studies are needed to determine whether this is a pharmacological response to the herb or a manifestation of a psychological effect. The latter interpretation seems likely inasmuch as pharmacokinetic studies have yet to demonstrate conclusively that passion flower contains any compound, or group of compounds, that penetrates into the brain following oral administration of the extract. For this reason, questions remain about the pharmacological value of this herb, the clinical and laboratory data notwithstanding.

Laboratory animal work also suggests that passion flower extract displays anticonvulsant, antidepressant, and analgesic activities. Because passion flower extract was found to reduce the amount of St. John’s wort needed to induce an antidepressant response in animal models, it was suggested that combined treatment with these two herbal supplements may yield a superior clinical response than can be achieved with either alone.

With regard to its anticonvulsant activity, in one study a Passiflora incarnata ethanol extract was shown to be effective in mice at a dose of 0.4 mg/kg, whereas in another the effective anticonvulsant dose of the same type of ethanol extract was between 150 and 600 mg/kg in mice. The large difference in doses with these ethanol extracts from the same plant species illustrates why many find it difficult to draw firm conclusions from such work. Such variations in findings do not normally occur if investigators use identical experimental protocols with a single, purified substance. They also would not be expected if passion flower produced significant quantities of a pharmacologically active agent that affects brain function.

It has been reported that orientin, a passion flower flavonoid, displays analgesic activity, whereas vitexin, another flavonoid, is inactive in conventional animal models of pain. It is doubtful this finding has any clinical significance because neither orientin nor vitrexin readily accumulates in the brain following oral administration, and analgesia is not an effect widely reported by humans during the several hundred years this herb has been consumed.

Studies aimed at defining a possible mechanism of action for the central nervous system effects of passion flower have focused on the brain GABA neurotransmitter system. Inasmuch as GABA is an inhibitory transmitter, agents that enhance its activity are known to relieve anxiety, induce sleep, and block seizures. Because all of these responses are reported for passion flower, an effect on GABA would provide a plausible explanation for its central nervous system actions. In fact, in vitro studies with passion flower extract indicate it affects components of the brain GABA system. The extract is reported to inhibit GABA accumulation into brain cells, which would prolong the action of this transmitter, to interact with GABA binding sites, and to induce GABA-like effects in rat brain slices. In vivo work in laboratory animals has also supported a possible interaction between passion flower herb and the brain GABA system. These in vivo and in vitro findings suggest that the extract contains a substance capable of directly activating brain GABA receptors. In fact, it is now known that the active constituent is GABA itself. As is true for many plants, passion flower, like mammalian brain, produces GABA. This means that GABA is present in the plant extract. Because of this, the in vitro results indicating that passion flower extract activates GABA receptors, interacts with GABA binding sites, and inhibits GABA accumulation in the brain can all be easily explained by the presence of GABA in the test sample. As GABA is not absorbed following oral administration, nor does it readily cross into the brain, the GABA in the passion flower extract cannot be responsible for any of the reported behavioral effects of this herb. Accordingly, the significance of the data suggesting that passion flower extract interacts with the brain GABA system is suspect unless the investigators demonstrate they have removed this amino acid from the experimental sample. As this is not routinely done, no definitive data exist indicating that passion flower extract selectively interacts with GABA or any other neurotransmitter system in the brain.

With regard to effects outside the central nervous system, there was for some time the belief that chrysin decreased estrogen levels. This idea resulted from the discovery that, in vitro, chrysin inhibits aromatase, an enzyme responsible for the conversion of testosterone to estrogens. If this occurred in vivo, such an effect could be exploited for treating some types of cancer and for increasing testosterone levels. This latter effect made chrysin-containing foods popular among men who thought such an action could increase their strength, energy, and sex drive. After years of study it was concluded that while chrysin is capable of inhibiting aromatase in vitro, it is inactive in vivo, most likely because of its poor bioavailability and rapid metabolism. This illustrates the importance of pharmacokinetics in determining the responses to drugs and natural products. It also demonstrates further that chrysin is an unlikely candidate as the passion flower component responsible for central nervous system effects.

Other responses to passion flower and its constituents that have been reported are a reduction in free radicals and an anti-inflammatory effect. Both of these actions are characteristics of many flavonoids. These effects are used to explain laboratory animal findings that passion flower extracts protect heart muscle from ischemic damage, display antiulcer activity, and are effective as treatments for inflammatory bowel disorder, allergies, and major depression. There are also suggestions that passion flower extract, or individual passion flower flavonoids, have antidiabetic and anticancer effects. As no definitive clinical studies support any of these uses, and it is known that the flavonoids shown to be active in vitro are poorly absorbed in humans, it seems unlikely that passion flower extract, or components thereof, are of any clinical value in the treatment of these conditions.

Adverse Effects
While in one clinical study it was noted that the administration of passion flower caused drowsiness, dizziness, and confusion in some subjects, the herb appears to be generally free of side effects when taken alone at the recommended dose. Given its potential to reduce central nervous system activity, caution should be exercised when taking passion flower in combination with drugs and other agents, such as alcohol, that are known to be sedating. This is illustrated by the report of an individual who experienced dizziness, tremor, and feelings of fatigue after consuming passion flower with valerian and lorazepam, both of which are known to decrease central nervous system activity.

Passion flower extract, and some of its individual components, can modify the absorption and excretion of drugs. Such effects are due to the interactions of the passion flower constituents with transport systems in the intestines and other tissues, and with their ability to modify the activity of liver enzymes responsible for drug metabolism. Although questions remain about the extent to which passion flower constituents enter the bloodstream after oral administration, and therefore the likelihood they will affect these drug transporters and metabolizing enzymes, the possibility exists that consumption of this herbal supplement, especially over extended periods, could influence responses to prescription medications that are taken at the same time.

Pharmacological Perspective
It is a fact that many individuals find consuming passion flower extract relieves tension and anxiety, and facilitates sleep. To deny this it would be necessary to ignore or discount the hundreds of years this herb was used for these purposes, both in prehistoric times and in the modern era. Moreover, there are ample laboratory animal and clinical data demonstrating these effects. What is uncertain is whether these actions represent a pharmacological response to chemicals contained in the passion flower extract or are, in humans at least, nonspecific behavioral effects that occur only in those who believe this herb has such beneficial actions. Behavioral studies on placebo responses demonstrate that humans are able to experience all types of emotions and to obtain symptomatic relief from numerous conditions, simply by believing, even if incorrectly, that they have consumed an effective medication. Such a placebo response could also explain the popularity of passion fruit among Native Americans. That is, cultural influences and expectations can have a significant effect on the behavioral response to any substance, whether or not it has a direct effect on the brain. The degree to which the responses to passion flower are psychologically, rather than pharmacologically, mediated remains unresolved given the experimental inconsistencies and contradictory findings with this substance, and the lack of success in identifying a chemical constituent responsible for these effects.

Some individuals are persuaded of the pharmacological actions of passion flower by the results from in vivo laboratory animal studies. After all, rats and mice are not likely to be psychologically primed to respond to this herb in a certain manner. However, there are many reasons such animal data cannot be taken as proof that a compound or plant extract has a particular effect in humans. Among these is the lack of information on the relative difference in the doses used in the laboratory as compared to those taken by humans. Without precise knowledge about the pharmacokinetic properties of the active constituent, it is impossible to know how much a human would have to swallow to consume an amount equivalent to what the laboratory animal receives when it is administered 600 mg/kg of the extract. While it is possible that some passion flower substances enter the brain and induce a behavioral response in rats when administered at this dose, such an effect would never occur clinically if the animal dose far exceeds the amount recommended for human use.

Administration of passion flower extract does have a calming effect for some individuals, although the scientific evidence supporting a pharmacological basis for this response is weak. The lack of solid laboratory and clinical data will not, and should not necessarily, deter the use of this product for those who find it beneficial. Nonetheless, many will remain skeptical about the value of this extract for any therapeutic purpose until one of its constituents is shown to exhibit the pharmacokinetic and pharmacodynamic properties expected of a substance, or of a defined mixture of plant constituents, that would be capable of altering behavior.

Read more: http://health.tipsdiscover.com/passion-flower-passiflora-incarnata-botany-therapeutic-uses-constituents-pharmaco-adverse-effects/#ixzz2h1L2qHGq

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