By Lina Fievet

Although it may be hard to spot this beautiful flower in a garden here in Europe, we can find passionflower in many herbal supplements and pills today in local health food stores or pharmacies. Discovered in South America and introduced in Europe by Spanish conquerors, it has since been used widely in western phytotherapy to help anxiety, nervousness and sleeping problems. In fact, passionflower contains many therapeutic compounds such as flavonoids and alkaloids that have sedative and anxiolytic properties.  It is thus not surprising that this flower has been used for such a long time all over the world. 

Introduction

Passiflora incarnata Linn., also known as Passionflower, are beautiful flowers found in Central or South America, with some species occurring in North America, Southeast Asia and Australia (Dhawan et al., 2001; Barnes et al., 2007).  The genus Passiflora comprises approximatively 520 species of plants belonging to the family Passifloraceae. Passiflora incarnata L. which is used medicinally, is rarely grown in Britain. The Blue Passionflower that can be found in the garden is in fact Passiflora caerulea, which cannot be used for medicinal purpose due to its toxicity. The flowers symbolize the “passion of Christ”, named after a spanish conquerors who discovered it from pre-Columbian people who used the plant to treat insomnia and nervousness (Miroddi et al., 2013; Jawna-Zboińska et al., 2016).

Popular History and Medicinal use

Among the different species of Passiflora, Passiflora incarnata L. is the most common one that is used in Western phytotherapy (Miroddi et al., 2013; Jawna-Zboińska et al., 2016). Some records indicates that the most ancient use of the plant dates back to the late Archaic period in North America, between 8000 and 20000 B.C.. The aboriginals, such as the Aztecs of Mexico or the Houmas of Louisiana in America, used the passionflower for its medicinal purposes. Passionflower was then brought to Europe by Spanish conquerors after its discovery in South America and was then introduced to European folk medicine to be used as a traditional and/or homeopathic remedy for the relief of mental stress, anxiety and sleeping disorders (Miroddi et al., 2013).

Traditionally, the aerial parts of passionflower were used as a sedative, anxiolytic and antispasmodic. Ulcers and hemorrhoids were also treated using aqueous extract of the root as a topical agent. Other traditional use of the whole plants was found for different conditions such as insomnia, anxiety and other central nervous system (CNS) disorders (Dhawan et al., 2001). The use of the plant in modern phytotherapy is summarized in table 1 below.

Table 1: therapeutic use of Passiflora incarnata L. in the world ((Miroddi et al., 2013)

Therapeutic indications	Places where this use was recorded
Insomnia	Turkey, North America, Vietnam, Australia, South America, Netherlands, Italy
Sedative	Argentina, Mexico, Brazil, EU, Vietnam, Rwanda, Congo, Kenya, Iraq, Australia, South America, Netherlands, Italy
Analgesic	Brazil, North America, Rwanda, Congo, Kenya
Menstrual problems (dysmenorrhoea, PMS)	Turkey, North America
Epilepsy	Turkey
Gastrointestinal problems	North America, Europe
Infections	Brazil, Europe
Muscle cramps	North America
Hysteria	North America
Anti-spasmodic	Brazil, Rwanda, Congo, Kenya
Overcoming morphine dependence	India
High blood pressure	Vietnam
Respiratory problems	India, Mexico, Argentina, Netherlands, South America, Italy, Brazil

Phytochemistry

According to the European Pharmacopoeia 7.5, the fragmented or cut, dried aerial parts are used, and may contain flowers and/or fruits (Barnes et al., 2007; Wichtl, 2004). However, the methanolic extract of leaves are the most effective as anxiolytic, and thus this part, excluding the flower and other plant parts, must be chosen (Dhawan et al., 2001).

Chemically, the aerial parts of passionflower contain up to 2.5% of flavonoids, such as  shaftoside, isoshaftoside, vitexin, isovitexine, orientine, iso-orientine, apigenin, kaempferol, vicenin, lucein, luteolin, quercetin and saponarin. The pharmacopoeial standard is not less than 1.5% expressed as Vitexin. The aerial part also contains indole alkaloids based on beta-carboline ring systemsuch as harman, harmin, harmalin, harmol and harmalol. Other constituents include phenolic acids, coumarins, phytosterols; fatty acids, linoleic/linelenic/palmitic/oleic/myristic acids; 1mL/kg essential oil, such as carvone, hexanol, linalol, eugenol, isoeugenol, etc.; cyanogenic glycosides; amino acids; sugars such as raffinose, sucrose, glucose, fructose, formic and butyric acids (Bruneton, 2016; Dhawan et al., 2001; Barnes et al., 2007).

Pharmacology

Monoaminergic neurotransmission

Monoaminergic neurotransmission with serotonin, norepinephrine and dopamine in the brain are important for the regulation of mood, reactivity to psychological stress, self-control, motivation, drive and cognitive performance. It is believed that the low concentration of these neurotransmitters cause depression and other affective disorders due to the decrease in monoaminergic neurotransmission in the brain (Hamon and Blier, 2013; Wecker, 2010).

Major depression and other anxiety disorders are generally treated with compounds that act in the brain to increase monoaminergic neurotransmission. One of them are monoamine oxidase inhibitors (MAOI), which inhibit the breakdown of serotonin, norepinephrine, tyramine and dopamine. By inhibiting the enzyme MAO, the concentration of neurotransmitters in the cytosol of the nerve terminal is increased, thus enhancing the aminergic activity (Wecker, 2010). The indole alkaloids present in Passiflora incarnata, such as harman, harmin, harmalin, harmol and harmalol, are thought to act as monoamine-oxidase inhibitors (Miroddi et al., 2013). The harman alkaloids, in particular, have been suggested to be the main bioactive phytoconstituents due to their MAO enzyme inhibiting properties (Dhawan et al., 2001).

GABA system

The stimulation of gamma-aminobutyric acid (GABA) receptors in the brain by GABA neurotransmitters results to the opening of the GABA receptors and influx of Cl- leading to a hyperpolarization of the postsynaptic cell. This in turn leads to the inhibition of the CNS resulting in anxiolytic and sedative effects. GABA receptors contain primary agonist binding site for GABA, and other allosteric sites for other compounds such as benzodiazepines, beta-carbolines, barbiturates etc (Wecker, 2010).

The sedative and anxiolytic activity of Passiflora incarnata L. can be due to the presence of flavonoids that might be acting as agonist on the GABA-benzodiazepine receptor (Dhawan et al., 2001; Bruneton, 2016; Appel et al., 2010). The presence of GABA was also observed in extracts of Passiflora incarnata L. (Grundmann et al., 2008; Elsas et al., 2010). Some researchers also showed that the administration of flumazenil, an antagonist of the GABA-A benzodiazepine binding site receptor, decreases the in vivo anxiolytic effect of Passiflora incarnata L.. This suggests that passionflower has a similar mechanism of action to that of diazepam, a benzodiazepine which act on GABA-A receptor (Miroddi et al., 2013; Appel et al., 2011).

Opioid and nicotinic receptors

Opioid analgesics are compounds that relieve moderate to severe pain. Activity of opioid peptides to opioid receptors results in inhibited neuronal activity and neuronal transmission, and thus contribute to its analgesic effect (Wecker, 2010). It was found that the analgesic activity of the extract of leaves of Passiflora incarnata L. may be mediated through the modulation of opioid receptors (Ingale and Kasture, 2012).

Pre-clinical data

Many pre-clinical tests were conducted on mice and rats to verify the effects of passionflower. In this section, we will review some of the most common therapeutic effects that were observed by the administration of passionflower extract.

In mice, it was shown that the methanol extracts of leaves, stems, flowers and whole plant had an anxiolytic effects (Dhawan et al., 2001). The anxiolytic effect in mice was also observed upon administration of the aqueous extract (Bruneton, 2016). Passionflower extracts were also found to prolong significantly sleep in mice and rats. Aqueous passionflower extract induced and potentiated sleep initiation in mice, although the hydroethanolic extract did not show such effect. (Ngan and Conduit, 2011. Soulimani et al., 1997). In rats, passionflower was shown to exert analgesic effects (Miroddi et al., 2013).

Other pre-clinical trials revealed that the administration of the plant extract to rats showed a significant dose-dependent decrease in seizure (Singh et al., 2012; Elsas et al., 2010), improved spatial learning, memory acquisition and short-term memory (Jawna-Zboińska et al., 2016). In mice, it was also reported that the plant extract could reverse tolerance and dependence to substances such as cannabinoid ∆-9 THC, diazepam, ethanol, morphine, and nicotine (Barnes et al., 2007), as well as anti-hyperglycemic activity with lowered glucose and LDL-cholesterol level (Gupta et al., 2012).

Clinical evidence

Existing clinical trials on anxiety

A 4-week double-blinded randomized trial testing passionflower tincture in 36 patients with Generalized Anxiety Disorder, compared to the benzodiazepine drug oxazolam, showed that there was no difference between the two groups. According to this trial, both herbal extract and oxazepam showed positive effects in decreased anxiety (Bruneton, 2016; Akhondzadeh et al., 2001). A clinical study that enrolled 60 patients, in which 30 people were treated with Passiflora incarnata L. 90 minutes before the surgery, showed that the anxiety was significantly lower in the passionflower group compared with the control group before surgery (Movafegh et al., 2008).  Aslanargun et al. also demonstrated a similar anxiolytic effect on patients before undergoing spinal anesthesia (Aslanargun et al., 2012). However, Cochrane concluded that the number of clinical trials showing the effectiveness of passionflower was too few in number to draw any conclusions (Miyasaka et al., 2017).

Existing clinical trials on sleep

In a randomized double-blind placebo control clinical study with 41 volunteers with insomnia, it was demonstrated that subjects received an infusion of dried Passiflora incarnata L.  (2g) had a significantly improved subjective sleep quality compared with the placebo group who were administered parsley (Miroddi et al., 2013; Ngan and Conduit, 2011). A small randomized double-blind vs. placebo clinical trial conducted on 12 females showed that diazepam, placebo and passionflower extract exhibited similar effects decreasing mental alertness and promoting sleep (Miroddi et al., 2013; Schulz et al., 1998).

Other clinical trials

A clinical double-blind randomized trial with placebo showed that the extract of Passiflora incarnata L. reduced mental symptoms, anxiety, agitation, irritability and craving associated with opiate withdrawal. Results from another clinical study involving 59 menopausal women also demonstrated that the passionflower extract had a positive effect of both bland on post-menopausal symptoms such as insomnia, depression, headaches etc. (Miroddi et al., 2013; Akhondzadeh et al, 2001).

Toxicity and side effects

The European Medicines Agency (EMA) reported that there is no observed toxicity for the extract of passionflower (Bruneton, 2016; European Medicines Agency, 2014). The use in pregnant and lactating mothers are not supported, as there are no data on the potential toxicity. However, some case reports in humans were reported showing some potential side effects. Some of them involved dizziness, drowsiness and confusion and reduced consciousness. A case report indicates severe side effects such as nausea, prolonged vomiting, weakness, drowsiness, ventricular arrhythmia and bradycardia. Passiflora incarnata L. also seem to be associated with IgE-mediated asthma and rhinitis. (Fisher et al., 2000; Carrasco et al., 2009 ).

Although interactions with other drugs have not been established, passionflower could have additive effects on sedation when used with drugs that have sedative activities. On the contrary, passionflower could also decrease the effects of stimulant drugs. For example, interactions between passionflower extract and amphetamines was shown induce a reduction in hyperactivity in rats. A study in rats also found that administration of passionflower extract and phenobarbital resulted in an additive sedative effect in rats. This effect was even greater when passionflower extract and kava extract (Piper methysticum) were both administered at the same time (Anon, 2013).

Use

The Committee for Herbal Medicinal Products (HMPC) of the EMA indicates the use of passionflower for the relief of stress and as an aid for sleep, based on traditional use. According to the HMPC monograph for the aerial parts of the passionflower, the comminuted herbal substance can be used as herbal tea orally, as well as in other herbal preparations in solid of liquid dosage forms for oral use. (European Medicines Agency, 2014).

Conclusion

Today, we can easily spot pills and tablets from the extract of passionflower at the pharmacy or in a health food store. Although many people do not know much about the flower, the plant offers many therapeutic potentials, such as for insomnia, anxiety and depression. As modern antidepressants and sleeping pills have been shown to have many undesirable side effects, herbal teas from the plant or tablets made from the extract could be a safe and effective alternative for anyone having stress, emotional or sleep problems.

Disclaimer: In this essay we do not to advise or recommend herbs for medicinal or health use. This information is intended for educational purposes only and should not be considered as a recommendation or an endorsement of any particular medical or health treatment. The use of any such product should be based on the appropriate advice of a health care professional or based on the information available in the patient information leaflets (i.e. for THR products).

©︎ Lina Fievet 2019. All rights reserved.

Lina Fievet is a MSc student in Medicinal Natural Products and Phytochemistry at the School of Pharmacy in University College London (2018-2019).

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