By Francis Brinker, ND
With the recent questionable discrediting of the safety of kava, a botanical shown to be effective in alleviating anxiety, interest in other alternatives to current medications for this condition has grown. A number of botanicals known for their "nervine" properties are being investigated. Nervine is an old term applied to botanical remedies known for their calming effects and relaxing aspects as mild sedatives. Studies with extracts of the aerial parts of passionflower, Passiflora incarnata, have shown promise for treating anxiety.
History of Medicinal Use
This particular species of passionflower is indigenous to the southeastern United States. It is a perennial tropical vine that was first introduced into clinical medicine in America in the late 19th century. Eclectic physicians and homeopaths helped popularize the use of alcoholic extracts of the fresh plant for nervousness, restlessness, and any over-excitement of the nervous system, especially for cases resulting in insomnia.1
The relatively late introduction of passionflower into the medical armamentarium—just prior to the dominance of pharmaceutical medications—in part led to its neglect outside of alternative methods of practice in America. Consequently, it never achieved status as an official drug in the United States Pharmacopeia. Although some naturopathic doctors and herbalists used it here and in Great Britain throughout the 20th century, its widespread incorporation into European medical practice resulted in an active scientific interest in its therapeutic potential. In 1985, passionflower received approval by the German Commission E for use as a remedy for "nervous restlessness."2
Laboratory Pharmacological Research
Identification of the sedative and anti-anxiety components of passionflower has been pursued in animal studies. Maltol has been proposed as an active component, but may actually be formed during heat-extraction processes.3 Freeze-dried hydroalcoholic and aqueous extract of passionflower fresh-frozen aerial (above ground) parts were tested by intraperitoneal injection for behavioral effects along with known constituents including harman alkaloids, flavonoids, and maltol.4 Whereas a 400 mg/kg dose of hydroalcoholic extract had anxiolytic properties, the aqueous extract showed sedative effects at 400 mg/kg and at 800 mg/kg induced sleep in mice given a sub-hypnotic dose of pentobarbital. Mixtures of maltol with alkaloids or with flavonoids produced neither sedative nor anxiolytic activity. Thus, it appears that extracts of the above-ground portion of the plant are more effective than partial mixtures of what are believed to be the active constituents.
Using bioactivity-directed fractionization and chromatography, dried and powdered aerial parts of passionflower were extracted with methanol.5 This extract was further sequentially extracted, but only the remaining methanol fraction retained any anxiolytic activity when administered orally to mice using the elevated plus-maze model. A sub-fraction of this portion showed anxiolytic activity at 10 mg/kg. Phytochemical screening found the active sub-fraction to be devoid of all known phytoconstituents, but contained a benzoflavone derivative of uncertain identity.
The mechanisms by which passionflower and its extracts and components influence mental conditions are not entirely understood. Passionflower extract is a dose-dependent competitive inhibitor of in vitro binding at central benzodiazepine sites, and inhibits binding at alpha-2 adrenoceptors.6 Another study found a commercial passionflower extract binds to central nervous system receptors sites for GABA-A and GABA-B, in addition to glycine, N-methyl-D-aspartate and quisqualate receptors, and chloride ion channel receptors.7
Several animal studies have shown that oral administration of passionflower products is an effective means of achieving neurological influence. In a murine model the sedative activity of an ethanolic extract was compared to an extract combining hydroalcoholic and aqueous extract fractions of the aerial parts of the plant.8 The measured effects were prolongation of pentobarbital sleeping time and onset of convulsions after pentylenetetrazole. Oral administration of the two passionflower extracts produced sedative effects when using 60 mg/kg of the multifraction extract, whereas four times as much of the ethanolic extract was required. A methanolic extract oral dose of 125 mg/kg of P. incarnata was as effective as 2 mg/kg diazepam in producing anxiolytic effects in mice.9 In contrast, petroleum ether, chloroform, and water extracts of this species and all four extracts of P. edulis, a close passionflower relative with similar appearance that is cultivated for its edible fruit, were ineffective in this test.
Clinical Studies
A recent double-blind, randomized, parallel-group trial in Iran compared 45 drops/d of a liquid extract of passionflower to 30 mg/d of oxazepam in treating generalized anxiety disorder.10 The study involved 20 women and 16 men ages 19-47 who satisfied DSM IV criteria for the diagnosis, along with a score of 14 or more on the Hamilton Anxiety Rating Scale, the principal measure of outcome. All psychotropic medication was stopped for at least seven days prior to study. Patients were assessed by a psychiatrist at baseline, day 4, and weekly after medication was initiated and subsequently administered over a four-week period. Compared to baseline, both the treatments significantly reduced anxiety scores with efficacy of oxazepam apparent from day 4 and that of passionflower extract from day 7. The differences between the two groups were only significant at day 4. As for adverse effects, impairment of job performance occurred significantly more often in the oxazepam group, but for total side effects there were no significant differences.
Some of these same investigators participated in another clinical trial utilizing the same passionflower liquid extract.11 In this double-blind, randomized, controlled trial, the use of 0.8 mg/d clonidine as the main therapy for treating opiate detoxification (along with 60 drops of placebo) was compared with the combination of clonidine and 60 drops daily of passionflower extract. The placebo and extract were given three times per day in divided doses. No other psychotropic medication was given. The patients were 65 males who fulfilled DSM IV criteria for opioid dependence. All were otherwise physically healthy, and those with affective disorder or a history of psychiatric problems were excluded. Opiate withdrawal severity was evaluated seven times over 14 days by a psychiatrist trained in using a modified Short Opiate Withdrawal Scale, which scored physical and behavioral symptoms (higher scores associated with worse symptoms). The behavioral symptoms evaluated were dysphoria, anxiety, agitation, irritability, and craving for substances.
On the basis of 10 physical symptoms, there were no significant differences between the two groups over the 14 days, though the passionflower group had consist-ently lower scores. For the five mental symptoms there were significantly higher mean mental scores on days 2, 3, 4, 7, and 14 for the clonidine group than for the group that used the passionflower extract. The total score average was significantly higher for clonidine than passionflower on day 14. Because benzodiazepines are not recommended for substance abuse withdrawal due to their own potential for inducing dependence, passionflower extract was considered a useful adjunct to standard therapy for managing emotional symptoms in opiate addiction.
Precautions and Interactions
The potential drowsiness caused by the sedative effects of passionflower may impair the ability to drive or operate machinery. Its safety for use during pregnancy or while nursing has not been established.3 The increased hypnotic effects of barbiturates when combined with hydroalcoholic and/or aqueous extracts of passionflower have been noted in animals.4,8
Adverse Effects
Since its introduction into medicine, passionflower and its extracts have been noted for their safety, with no side effects observed following any applications.1 The German Commission E monograph indicated that no side effects were known;2 however, a work published by the Canadian Pharmacists Association in conjunction with the Canadian Medical Association noted that drowsiness may occur. One case of hypersensitivity vasculitis has been documented.3
The previously cited clinical anxiety study found mild-to-moderate impairment of job performance in eight of 16 subject in the passionflower group, but this was less significant than the five mild-to-moderate and six severe job performance problems found in 15 participants using oxazepam.10 The other most common complaints after using the extract were dizziness (7), drowsiness (6), and confusion (4), and were equivalent to oxazepam users in number (8, 7, and 4, respectively) but of less severity.
A single case of severe nausea, vomiting, drowsiness, prolonged QTc segment, and brief episodes of ventricular tachycardia associated with passionflower use has been reported.12 Tablets from the product obtained from this patient were analyzed and found consistent with expected chromatographic profiles, and no digitoxin or digoxin was detected. Theoretically, the harman alkaloid components might have been responsible, if the patient had a specific polymorphic variation of genes for cytochrome P450 isozymes. Harman alkaloid content varies but should not exceed 0.01%.2
Formulation and Dosage
The Commission E dosage recommendation is 4-8 g daily of the above-ground plant parts made into a tea, or equivalent preparations.2 Based on existing pharmacological research, a water extract is more likely to have sedative activity than anti-anxiety effects.4,8
Anxiolytic activity has been demonstrated with hydoalcoholic and methanolic extracts in animals.4,5,9 The clinical trials demonstrating anti-anxiety effect utilized a liquid (likely hydroalcoholic) extract of undefined strength in doses of 45-60 drops daily (depending on the drop size, 2-4 mL), given in three divided doses.10,11
General adult doses of hydroalcoholic liquid extracts include 1-4 mL of a 1:8 tincture 3-4 times daily, or, 0.5-1.0 mL of a 1:1 liquid extract (made with 25% alcohol) three times daily. Children 3-12 years of age should receive a portion of the adult dose calculated according to body weight.3
Conclusion
Passionflower has a history of use as a safe, mild sedative when used as a tea or tincture, especially for treating insomnia. Recent clinical studies have shown that a liquid extract is effective in helping to relieve anxiety as well as for ameliorating mental withdrawal symptoms associated with substance abuse. Hydroalcoholic extracts have been shown to relieve anxiety symptoms, whereas a tea made from the herb has more of a sedative effect.
Recommendation
Choosing passionflower for the treatment of anxiety is not based on its dramatic potency, but, as with many herbs, is due to its efficacy for managing conditions with adequate strength and relative safety. Employed on a clinical trial basis in cases of mild anxiety, passionflower hydroalcoholic extracts given throughout the day for 1-2 weeks can provide effective relief from this common condition. Taken at bedtime when necessary, especially after loss of sleep resulting from worry, passionflower as a tea provides a relaxing nightcap. Use of the herb or tea during pregnancy or lactation, before driving, or with alcohol or sedative drugs should be avoided.
Dr. Brinker is an Instructor at the Program in Integrative Medicine at the University of Arizona, Tucson.
References
1. Gibson WS. Passiflora incarnata. Eclectic Med J 1892; 52:216.
2. Blumenthal M, et al, eds. The Complete German Commission E Monographs. Austin, TX: American Botanical Council; 1998.
3. Smith M. Passionflower. Herbs—Everyday Reference for Health Professionals. Ottawa: Canadian Pharmaceutical Association, Canadian Medical Association; 2000.
4. Soulimani R, et al. Behavioural effects of Passiflora incarnata L. and its indole alkaloid and flavonoid derivatives and maltol in the mouse. J Ethnopharmacol 1997;57:11-20.
5. Dhawan K, et al. Anti-anxiety studies on extracts of Passiflora incarnata Linneaus. J Ethnopharmacol 2001;78: 165-170.
6. Valli M, et al. Euphytose, an association of plant extracts with anxiolytic activity: Investigation of its mechanism of acton by an in vitro binding study. Phytother Res 1991;5: 241-244.
7. Cott J. Medicinal plants and dietary supplements: Sources for innovative treatments or adjuncts? Psycho-pharmacol Bull 1995;31:131-137.
8. Speroni E, et al. Sedative effects of crude extract of Passiflora incarnata after oral administration. Phytother Res 1996;19:A92-A94.
9. Dhawan K, et al. Comparative biological activity study on Passiflora incarnata and P. edulis. Fitoterapia 2001;72: 698-702.
10. Akhondzadeh S, et al. Passionflower in the treatment of generalized anxiety: A pilot double-blind randomized controlled trial with oxazepam. J Clin Pharm Ther 2001;26: 363-367.
11. Akhondzadeh S, et al. Passionflower in the treatment of opiates withdrawal: A double-blind randomized controlled trial. J Clin Pharm Ther 2001;26:369-373.
12. Fisher AA, et al. Toxicity of Passiflora incarnata L. Clin Toxicol 2000;38:63-66.
Brinker F. Passionflower liquid extract for anxiety. Altern Med Alert 2003;6(11):125-128.
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