Medication Guide App

Lobelia

Scientific Name(s): Lobelia inflata L., Campanulaceae (harebell family)

Common Name(s): Indian tobacco , Indian weed , pukeweed , asthma weed , gagroot , vomitwort , bladderpod , eyebright

Uses

Lobelia inflata and its major alkaloid, lobeline, have been used in smoking cessation programs and have been proposed for treatment of other drug dependencies; however, there is only modest evidence for efficacy.

Dosing

Clinical studies of lobeline for smoking withdrawal used doses of 5 mg twice daily, with 0.5 mg lozenges used in addition when there was an urge to smoke. The useful dose of lobeline is very close to the toxic dose. In use of the whole plant, minor variations in alkaloid content could increase the potential for toxicity.

Contraindications

Contraindications have not yet been identified.

Pregnancy/Lactation

Documented adverse effects include loss of uterine tone. Avoid use.

Interactions

None well documented.

Adverse Reactions

Lobelia and lobeline are capable of inducing nausea, vomiting, and dizziness at high doses (8 mg lobeline sulfate).

Toxicology

The therapeutic dose of lobeline is very close to the toxic dose.

Botany

Lobelia is a branching, perennial herb that is completely self-fertilizing and reproduces only once in its lifetime (monocarpy). 1 It grows from 0.3 to 0.9 m in height and produces small, violet-pinkish flowers in the alternate leaf axils. The base of the flowers expands to form the seed capsule, which is the source of the name “inflata.” It is found in the eastern United States and Canada from Georgia and Arkansas to Labrador. There are no recent clinical studies to support specific dosage of linden. Classical use of the flowers was at a dosage of 2 to 4 g daily in a tea for coughs and colds. 2

History

American Indians smoked the leaves as tobacco and used them medicinally for respiratory ailments. Similar folk uses for asthma, chronic bronchitis, whooping cough, cholera, and many other conditions were recorded. Lobelia 's emetic properties were well known in the nineteenth century. There are no recent clinical studies to support specific dosage of linden. Classical use of the flowers was at a dosage of 2 to 4 g daily in a tea for coughs and colds. 3

Chemistry

The piperidine alkaloid lobeline was isolated as the main active component of Lobelia in 1921. 4 Its absolute stereochemistry was determined in 1965. 5 A number of related alkaloids also have been isolated, including lobelanine and lobelanidine. 2 These alkaloids are present in several other species of Lobelia , with lobeline a major constituent in all of them. 2 The triterpene ester beta-amyrin palmitate has been reported from L. inflata , 6 while several polyacetylenes have been identified in plant tissue culture. 7

Uses and Pharmacology

The primary bioactive component of Lobelia is the alkaloid lobeline, although the minor alkaloids have been shown to have similar but distinct pharmacology in a number of nicotinic cholinergic systems. The following discussion focuses on the activities of lobeline.

Smoking cessation

Lobeline has been found to bind to neuronal nicotinic cholinergic receptor preparations with low nanomolar affinity, and structure-activity studies of analogs have explored the structural requirements for nicotinic receptor-binding activity. 8

Animal data

Vast pharmacologic literature exists for lobeline, which has long been classified as a nicotinic receptor ligand. 9 However, it has become clear that there is a large diversity of nicotinic receptor subtypes that differ in subunit composition and function and that lobeline's actions are only partly caused by agonism at nicotinic receptors. 10 A panel of subunit combinations was found to vary in affinities for lobeline as well as for other nicotinic ligands. 11 However, the homomeric α 7 nicotinic receptor was insensitive to lobeline as an agonist. 12

In more complex experimental systems, lobeline behaved differently from nicotine, inhibiting dopamine uptake into synaptosomes and depleting levels of dopamine in rat striatal slices. 13 In nicotine-pretreated rats, lobeline appeared to act as a short-acting antagonist of nicotinic receptors, mediating the effects of nicotine on mesolimbic dopamine activity and locomotor stimulation. 14 In freely moving rats, lobeline did not attenuate dopamine release from striatum as nicotine did, as measured by microdialysis. 15 Similarly, nicotine increased release of acetylcholine in rat hippocampal microdialysis, while lobeline had no effect. 16 The effects of lobeline on N -methyl-D-aspartate (NMDA), 17 serotonin, 18 and norepinephrine 19 release have been reported to be complicated phenomena.

Clinical data

Lobeline was a component of OTC products for withdrawal from tobacco addiction for many years. Results from clinical studies of the efficacy of lobeline have been mixed, 20 , 21 , 22 and a meta-review found that none of the available studies have been controlled adequately or were of sufficient duration to prove its efficacy. 23 The FDA removed lobeline from the market because of lack of demonstrated efficacy as part of its OTC review process in 1993. 23

Amphetamine abuse
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. Lobeline attenuated the self-administration of amphetamine, but not sucrose, by rats. 24 In several rodent models, lobeline had a selective effect on amphetamine-induced behavior and neurochemistry. 25 The postulated mechanism of activity in this context is inhibition of dopamine uptake and promotion of dopamine release from presynaptic storage vesicles. 26 Limitations of lobeline may include the observation of self-administration in drug-näive mice 27 and the fact that cross-tolerance to nicotine has been observed. 8

Clinical data

The addiction liability of lobeline in humans has not been established.

Other uses
Respiratory effects

Lobeline's effects on respiratory physiology may be responsible for its initial use in smoking cessation. Stimulation of respiration and bronchoconstriction are observed with lobeline and nicotine. 28 At high doses, lobeline induces sensations of choking or breathlessness. 29 , 30

Analgesia

A role for spinal nicotinic receptor subtypes in nonopioid analgesia has been found using the frog alkaloid epibatidine, and lobeline inhibited its analgesic properties, but potentiated epibatidine-induced agitation. 31 , 32 , 33

Memory, learning, and anxiety

Lobeline has been studied for its ability to improve learning and memory. Mice treated with lobeline for 5 days before training showed improved performance in a water maze; however, the effect was limited to younger mice. 34 Lobeline, along with other nicotinic agonists, has been shown to improve performance in memory function in animal experiments. 35 Lobeline also has been found to have activity along with nicotine in anxiolytic models. 36 Identification of the specific nicotinic subtypes involved may lead to better understanding of the mechanism of these effects. One unconfirmed study attributed antidepressant activity to a fatty acid ester of a common triterpene; however, no further work has substantiated this report. 6

Dosage

There is no recent clinical evidence to support use of lobelia. Lobeline was withdrawn from OTC use in 1993 by the FDA. Clinical studies of lobeline for smoking withdrawal administered doses of 5 mg twice a day, with 0.5 mg lozenges used in addition when the urge to smoke was perceived. 37

Pregnancy/Lactation

Documented adverse effects include loss of uterine tone. Avoid use. 38

Interactions

None well documented.

Adverse Reactions

As might be deduced from the common names for the plant, Lobelia and lobeline are capable of inducing nausea, vomiting, and dizziness at high doses (8 mg lobeline sulfate). 23

Toxicology

Clinical studies of lobeline for smoking withdrawal used doses of 5 mg twice daily, with 0.5 mg lozenges used in addition when there was an urge to smoke. 22 Thus, the therapeutic dose of lobeline is very close to the toxic dose. In use of the whole plant, minor variations in alkaloid content could increase the potential for toxicity.

Bibliography

1. Simons AM, Johnston MO. Plasticity and the genetics of reproductive behaviour in the monocarpic perennial, Lobelia inflata (Indian tobacco). Heredity . 2000;85(pt 4):356-365
2. Krochmal A, Wilken L, Chien M. Lobeline content of four Appalachian lobelias. Lloydia . 1972;35:303-304.
3. Bolyard JL. Medicinal Plants and Home Remedies of Appalachia . Springfield, IL: Charles C. Thomas; 1981:51-53.
4. Wieland H. Alkaloids of the lobelia plant. (Preliminary communication.) Chem Ber . 1921;54B:1784.
5. Schöpf C, et al. Absolute configuration of (-)-lobeline and of its reduction products. Ann Chem . 1965;63:18184-18185.
6. Subarnas A, Oshima Y, Sidik, Ohizumi Y. An antidepressant principle of Lobelia inflata L. (Campanulaceae). J Pharm Sci . 1992;81:620-621.
7. Ishimaru K, Yonemitsu H, Shimomura K. Lobetyolin and lobetyol from hairy root culture of Lobelia inflata . Phytochemistry . 1991;30:2255-2257.
8. Flammia D, Dukat M, Damaj MI, Martin B, Glennon RA. Lobeline: structure-affinity investigation of nicotinic acetylcholinergic receptor binding. J Med Chem . 1999;42:3726-3731.
9. Damaj MI, Patrick GS, Creasy KR, Martin BR. Pharmacology of lobeline, a nicotinic receptor ligand. J Pharmacol Exp Ther . 1997;282:410-419.
10. Decker MW, Brioni JD, Bannon AW, Arneric SP. Diversity of neuronal nicotinic acetylcholine receptors: lessons from behavior and implications for CNS therapies. Life Sci . 1995;56:545-570.
11. Parker MJ, Beck A, Luetje CW. Neuronal nicotinic receptor β2 and β4 subunits confer large differences in agonist binding affinity. Mol Pharmacol . 1998;54:1132-1139.
12. Briggs CA, McKenna DG. Activation and inhibition of the human α7 nicotinic acetylcholine receptor by agonists. Neuropharmacology . 1998;37:1095-1102.
13. Teng L, Crooks PA, Sonsalla PK, Dwoskin LP. Lobeline and nicotine evoke [ 3 H]overflow from rat striatal slices preloaded with [ 3 H]dopamine: differential inhibition of synaptosomal and vesicular [ 3 H]dopamine uptake. J Pharmacol Exp Ther . 1997;280:1432-1444.
14. 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;125:1115-1119.
15. 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;39:88-98.
16. 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;351:181-188.
17. 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;36:39-50.
18. 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 [ 3 H]5-HT from rat hippocampal slices. Neuropharmacology . 1996;35:1769-1777.
19. 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;294:302-307.
20. Grabowski J, Hall SM. Tobacco use, treatment strategies, and pharmacological adjuncts: an overview. NIDA Res Monogr . 1985;53:1-14.
21. Schuster CR, Lucchesi BR, Emley GS. The effects of d -amphetamine, meprobamate, and lobeline on the cigarette smoking behavior of normal human subjects. NIDA Res Monogr . 1979;91-99.
22. Plakun Al, Ambrus J, Bross I, Graham S, Levin ML, Ross CA. Clinical factors in smoking withdrawal: preliminary report. Am J Public Health Nations Health . 1966;56:434.
23. Stead LF, Hughes JR. Lobeline for smoking cessation. Cochrane Database Syst Rev . 2000;CD000124.
24. Harrod SB, Dwoskin LP, Crooks PA, Klebaur JE, Bardo MT. Lobeline attenuates d -methamphetamine self-administration in rats. J Pharmacol Exp Ther . 2001;298:172-179.
25. Miller DK, Crooks PA, Teng L, et al. Lobeline inhibits the neurochemical and behavioral effects of amphetamine. J Pharmacol Exp Ther . 2001;296:1023-1034.
26. Dwoskin LP, Crooks PA. A novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse. Biochem Pharmacol . 2002;63:89-98.
27. Rasmussen T, Swedberg MD. Reinforcing effects of nicotinic compounds: intravenous self-administration in drug-näive mice. Pharmacol Biochem Behav . 1998;60:567-573.
28. Klide AM, Aviado DM. Carotid receptors and bronchomotor responses. Effects of cigarette smoke, lobeline, and cyanide. Arch Environ Health . 1968;17:65-70.
29. Raj H, Singh VK, Anand A, Paintal AS. Sensory origin of lobeline-induced sensation: a correlative study in man and cat. J Physiol . 1995;482(pt 1):235-246.
30. Butler JE, Anand A, Crawford MR, et al. Changes in respiratory sensations induced by lobeline after human bilateral lung transplantation. J Physiol . 2001;534:583-593.
31. Khan IM, Buerkle H, Taylor P, Yaksh TL. Nociceptive and antinociceptive responses to intrathecally administered nicotinic agonists. Neuropharmacology . 1998;37:1515-1525.
32. Khan IM, Stanislaus S, Zhang L, Taylor P, Yaksh TL. A-85380 and epibatidine each interact with disparate spinal nicotinic receptor subtypes to achieve analgesia and nociception. J Pharmacol Exp Ther . 2001;297:230-239.
33. Damaj MI, Fei-Yin M, Dukat M, Glassco W, Glennon RA, Martin BR. Antinociceptive responses to nicotinic acetylcholine receptor ligands after systemic and intrathecal administration in mice. J Pharmacol Exp Ther . 1998;284:1058-1065.
34. Vicens P, Bernal MC, Carrasco MC, Redolat R. Effects of lobeline on spatial learning in C57BL mice. Neurosci Res Commun . 2000;27:9-19.
35. Levin ED. Nicotinic agonist and antagonist effects on memory. Drug Dev Res . 1996;38:188-195.
36. Brioni JD, O'Neill AB, Kim DJ, Decker MW. Nicotinic receptor agonists exhibit anxiolytic-like effects on the elevated plus-maze test. Eur J Pharmacol . 1993;238:1-8.
37. Plakun AL, et al. Clinical factors in smoking withdrawal: preliminary report. Am J Public Health Nations Health . 1966;56:434.
38. Ernst E. Herbal medicinal products during pregnancy: are they safe? BJOG . 2002;109:227-235.

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