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Lobelia

Scientific Name(s): Lobelia inflata L.
Common Name(s): Herba Lobellae Chinensis, Asthma weed, Bladderpod, Chinese Lobelia , Eyebright, Gagroot, Indian tobacco, Indian weed, Pukeweed, Vomitwort

Clinical Overview

Use

L. inflata and its major alkaloid, lobeline, have been used in smoking cessation programs and have been proposed for treatment of other drug dependencies; however, clinical evidence is limited.

Dosing

There is no recent clinical evidence to support the use of lobelia. The sale of OTC lobeline products for smoking cessation was prohibited by the US Food and Drug Administration (FDA) in 1993.

Traditional use of the leaf (eg, as an expectorant) suggests 100 mg of dry herb up to 3 times a day. However, there are no clinical trials to support this use. Doses of 0.6 to 1 g leaf are considered toxic, while 4 g of leaf is considered to be fatal.

Contraindications

Contraindications have not been defined; however, the sale of lobelia OTC products for smoking cessation is prohibited by the FDA due to a lack of efficacy and safety evidence.

Pregnancy/Lactation

Avoid use. Documented adverse effects, including loss of uterine tone and lack of safety evidence.

Interactions

None well documented.

Adverse Reactions

Lobelia and lobeline are capable of inducing nausea, vomiting, tremors, and dizziness at high doses. Lobelia alkaloids are cardioactive, and cardiotoxicities, including hypotension, tachycardia, and convulsion, have been reported. Contact dermatitis has also been reported.

Toxicology

Toxic dosages of the plant have been described: 1 g of leaf is toxic, while 4 g of leaf is considered to be a fatal dose. The alkaloid lobeline was not genotoxic or mutagenic in 1 study, and liver and kidney biochemistry in mice appeared unaffected.

Botany

L. inflata is a branching, perennial herb that is completely self-fertilizing and reproduces only once in its lifetime.1 It grows from 0.3 to 0.9 m tall and produces small, violet-pinkish flowers in the alternate leaf axils. The base of the flower expands to form the seed capsule, which is the source of the name "inflata." It is native to the eastern half of United States and parts of Canada.2, 3 The genus Lobelia has more than 400 recognized species, some of which contain alkaloids similar to those of L. inflata, including Livistona chinensis, a plant important in traditional Chinese medicine.3

History

The plant was named in honor of Matthias de Lobel, a 16th century Flemish physician and botanist, and is native to North America. American Indians smoked the leaves like tobacco and used them medicinally for respiratory ailments. Lobelia was introduced into New England medical practice in the 18th century to produce emesis. It was also used in treating colic, rheumatism, fever, and asthma. By the 19th century, lobelia was considered an important medicinal plant used in many conditions (eg, abscess, insomnia, tetanus, shock); however, fatalities were recorded due to dosing inconsistencies.4, 5 In 1993, the sale of lobelia OTC products for smoking cessation was prohibited by the FDA.3, 6, 7

Chemistry

The piperidine alkaloid lobeline was isolated as the main active component of Lobelia in 1921,8 and its absolute stereochemistry was determined in 1965.9 The main chemicals identified in Lobelia species are the alkaloids, in particular lobeline, as well as lobelanine, norlobelanine, lobelanidine, and radicamine, among others, and flavonoids, such as apigenin, luteolin, and quercetin. Other compounds include terpenes, alkynes, coumarins, and mineral elements.10, 11, 12 Lobeline concentration is highest in the seeds of the plant.13 Antiviral activity observed in L. chinensis has been attributed to lobechine and scoparone.14

Uses and Pharmacology

Lobeline has a high affinity for nicotinic acetylcholine receptors, and exhibits both agonist and antagonistic actions.13, 15, 16, 17 However, because a large diversity of nicotinic receptor subtypes have been identified, lobeline's actions are now thought to be only partly caused by agonism at nicotinic receptors, with some subtypes insensitive to lobeline.18, 19, 20 Similarly to nicotine, stimulation of respiration and bronchoconstriction have been observed with lobeline21; however, lobeline exhibits a slow off rate from receptors17 and probably acts via a different mechanism than does nicotine.13, 22 The effects of lobeline on N-methyl-D-aspartate,23 and [3H]5-HT,24 and norepinephrine25 release have been described. A review of potential mechanisms of action has been published.13

Addiction, psychostimulant

Animal data

Experimental work has provided evidence that lobeline may be useful in the treatment of amphetamine abuse, based on the blockade of amphetamine-induced dopamine release in rat striatum, and the observed high affinity of lobeline for opioid receptors.13, 26 Lobeline attenuated the self-administration of amphetamine, methamphetamine, and heroin by rats.26, 27, 28, 29 In several rodent models, lobeline had a selective effect on amphetamine-induced behavior and neurochemistry.30 Limitations of lobeline may include the observation of self-administration in drug-naive mice,31 although disputed,13 and the fact that cross-tolerance to nicotine has been observed.15

Clinical data

There are no clinical data regarding the use of lobeline or lobelia extracts in management of psychostimulant abuse. The addiction liability of lobeline in humans has not been established.

Addiction, tobacco

Animal data

Experiments in rodents and in vitro studies have produced equivocal results, possibly reflecting a diversity of experimental procedures, as well as actions of lobeline on receptor sites.13, 32, 33, 34

Clinical data

Lobeline was a component of OTC products for smoking cessation for many years. Results from clinical studies of the efficacy of lobeline have been mixed,35, 36, 37 and a meta-review found that none of the available studies were adequately controlled or of sufficient duration to prove its efficacy.38, 39 The FDA required the removal of lobeline products for smoking cessation from the market because of lack of demonstrated efficacy as part of its OTC review process in 1993.6

CNS, other effects

Animal data

Experiments have shown lobeline to exert analgesic,40, 41 enhanced memory and learning,42, 43 antidepressant,44 and anxiolytic effects.5, 13, 45, 46 Lobeline has also been shown to reduce seizures in mice, possibly by increasing the levels of gamma-aminobutyric acid in the brain.47

Clinical data

A small study (N = 42) evaluated the effect of lobeline in attention deficit hyperactivity disorder (ADHD) compared with placebo and methylphenidate. No discernable difference could be found; however, the small study size could be responsible for the lack of effect.46 There are no clinical data on the use of lobeline in epilepsy.

Other uses

Antiviral activity

Orally administered lobeline inhibited herpes simplex virus (HSV) 1 replication in mice (decreased HSV titre)48 and in vitro.14

Cancer

Lobeline and extracts of L. chinensis have been studied in vitro and in rodents for anticancer activity. In mice, an extract of L. chinensis inhibited growth of liver and gastric cancers12 and reduced the number of precancerous colon lesions.49 In human cancer cell lines, lobeline showed potential in reversing P-glycoprotein transporter–dependent multidrug resistance.50

Respiratory effects

Lobeline was traditionally used for the management of respiratory conditions, such as pneumonia, asthma, and bronchitis, because it induces coughing and consequent expectorant action.5 With the development of more effective agents, use of lobelia became obsolete. However, a group of researchers reported on the effect of lobeline on juxtapulmonary receptors using intravenous (IV) bolus administrations.51

Dosing

There is no recent clinical evidence to support the use of lobelia. The sale of OTC lobeline products for smoking cessation was prohibited by the US FDA in 1993.6

A study among patients with ADHD used daily doses of lobeline (salt form undefined) 7.5, 15, and 30 mg for 7 days.46 IV lobeline as a bolus has been used in limited clinical studies at doses of up to 100 mcg/kg (a mean dose of 45 mcg/kg [+/-23 mcg] produced a distinct dry cough).51

Traditional use of the leaf (eg, as an expectorant) suggests 100 mg of dry herb up to a maximum of 3 times a day.7 Doses of 0.6 to 1 g of leaf are considered toxic, while 4 g of leaf is considered to be fatal.7

Pregnancy / Lactation

Avoid use. Documented adverse effects, including loss of uterine tone,52 and lack of safety evidence.7

Interactions

None well documented.

Adverse Reactions

Lobelia and lobeline are capable of inducing nausea, vomiting, tremors, and dizziness at high doses (lobeline sulfate 8 mg).7 Respiratory effects have also been described; at high doses, lobeline can induce sensations of choking or breathlessness.51, 53 The lobelia alkaloids are cardioactive, and cardiotoxicities, including hypotension, tachycardia, and convulsion, have been reported.54, 55 Death from overdose has been recorded in historical literature; however, reports in the medical literature are lacking.3, 7 In 1993, sale of lobelia OTC products for smoking cessation was prohibited by the FDA due to a lack of efficacy and safety evidence.3, 6, 7, 38 Contact dermatitis has been reported.56

Toxicology

Toxic doses of the plant have been described (1 g of leaf as toxic, while 4 g of leaf is considered to be fatal).7 The alkaloid lobeline was not genotoxic or mutagenic in 1 study,57, 58 and liver and kidney biochemistry in mice appeared unaffected.57, 58

References

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6. Food and Drug Administration, HHS. Drug products containing active ingredients offered over the counter (OTC) for use as a smoking deterrent. 2014 Apr 1;21(5):21CFR310.544
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8. Wieland H. Alkaloids of the lobelia plant (preliminary communication). Chem Ber. 1921;54B:1784.
9. Schöpf C, et al. Absolute configuration of (-)-lobeline and of its reduction products. Ann Chem. 1965;63:18184-18185.
10. Duke J. Dr. Duke's phytochemical and ethnobotanical databases. http://www.ars-grin.gov/duke/. Accessed April 1, 2014.
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22. Teng L, Crooks PA, Sonsalla PK, Dwoskin LP. Lobeline and nicotine evoke [3H]overflow from rat striatal slices preloaded with [3H]dopamine: differential inhibition of synaptosomal and vesicular [3H]dopamine uptake. J Pharmacol Exp Ther. 1997;280:1432-1444.9067333
23. Rao TS, Correa LD, Lloyd GK. Effects of lobeline and dimethylphenylpiperazinium iodide (DMPP) on N-methyl-D-aspartate (NMDA)-evoked acetylcholine release in vitro: evidence for a lack of involvement of classical neuronal nicotinic acetylcholine receptors. Neuropharmacology. 1997;36(1):39-50.9144640
24. Lendvai B, Sershen H, Lajtha A, Santha E, Baranyi M, Vizi ES. Differential mechanism involved in the effect of nicotinic agonists DMPP and lobeline to release [3H]5-HT from rat hippocampal slices. Neuropharmacology. 1996;35(12):1769-1777.9076756
25. Sántha E, Sperlágh B, Zelles T, et al. Multiple cellular mechanisms mediate the effect of lobeline on the release of norepinephrine. J Pharmacol Exp Ther. 2000;294(1):302-307.10871326
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27. Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT. Lobeline attenuates d-methamphetamine self-administration in rats. J Pharmacol Exp Ther. 2001;298(1):172-179.11408539
28. Nickell JR, Siripurapu KB, Vartak A, Crooks PA, Dwoskin LP. The vesicular monoamine transporter-2: An important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse. Adv Pharmacol. 2014;69:71-106.24484975
29. Neugebauer NM, Harrod SB, Stairs DJ, Crooks PA, Dwoskin LP, Bardo MT. Lobelane decreases methamphetamine self-administration in rats. Eur J Pharmacol. 2007;571(1):33-38.17612524
30. Miller DK, Crooks PA, Teng L, et al. Lobeline inhibits the neurochemical and behavioral effects of amphetamine. J Pharmacol Exp Ther. 2001;296(3):1023-1034.11181937
31. Rasmussen T, Swedberg MD. Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-naive mice. Pharmacol Biochem Behav. 1998;60(2):567-573.9632242
32. Benwell ME, Balfour DJ. The influence of lobeline on nucleus accumbens dopamine and locomotor responses to nicotine in nicotine-pretreated rats. Br J Pharmacol. 1998;125(6):1115-1119.9863636
33. Lecca D, Shim I, Costa E, Javaid JI. Striatal application of nicotine, but not of lobeline, attenuates dopamine release in freely moving rats. Neuropharmacology. 2000;39(1):88-98.
34. Tani Y, Saito K, Imoto M, Ohno T. Pharmacological characterization of nicotinic receptor-mediated acetylcholine release in rat brain—an in vivo microdialysis study. Eur J Pharmacol. 1998;351(2):181-188.9687001
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This information relates to an herbal, vitamin, mineral or other dietary supplement. This product has not been reviewed by the FDA to determine whether it is safe or effective and is not subject to the quality standards and safety information collection standards that are applicable to most prescription drugs. This information should not be used to decide whether or not to take this product. This information does not endorse this product as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this product. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this product. This information is not specific medical advice and does not replace information you receive from your health care provider. You should talk with your health care provider for complete information about the risks and benefits of using this product.

This product may adversely interact with certain health and medical conditions, other prescription and over-the-counter drugs, foods, or other dietary supplements. This product may be unsafe when used before surgery or other medical procedures. It is important to fully inform your doctor about the herbal, vitamins, mineral or any other supplements you are taking before any kind of surgery or medical procedure. With the exception of certain products that are generally recognized as safe in normal quantities, including use of folic acid and prenatal vitamins during pregnancy, this product has not been sufficiently studied to determine whether it is safe to use during pregnancy or nursing or by persons younger than 2 years of age.

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