Lobelia

The Iroquois used the root for venereal disease, ulcers and leg sores, and applied the mashed leaves as a poultice to an abscess at the side of the neck. The Cherokee made a poultice of the mashed roots for body aches, and rubbed the leaves on sores, aches, stiff necks and chapped skin. The Crow used the plant in religious ceremony ^{24Reference 24Anderson · 2000Indian tobacco, Lobelia inflata L. — plant guideView study →}.

Native peoples were said to have smoked and chewed the leaves ^{23Reference 23Lady Bird Johnson Wildflower CenterLady Bird Johnson Wildflower Center. (n.d.). Lobelia inflata (Indian tobacco) — plant database entry. Native Plant Information Network, University of Texas at Austin. https://www.wildflower.org/plants/result.php?id_plant=LOINView study →}. The Penobscot knew the plant, and it was used in New England home medicine before Samuel Thomson made it famous ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Samuel Thomson and Manasseh Cutler brought lobelia into medical practice in the late eighteenth and early nineteenth centuries. They called it emetic weed and emetic herb, and the names puke weed and vomit weed followed. Cutler, who suffered from asthma, found it gave him more relief than any other remedy, and published the first account of it in 1785 ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Thomson was tried after a patient, Ezra Lovett, died under his care, and the prosecution accused him of killing Lovett with lobelia. Thomson said the drug had been marsh rosemary, the powder produced in court proved to be marsh rosemary, and the judge directed the jury to acquit. A second physician, R. K. Frost of New York, was convicted of manslaughter in 1837 after a patient died under lobelia treatment ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Lobelia was official in the first United States Pharmacopoeia of 1820 ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}. King’s American Dispensatory (1898) calls it the first of remedies for spasmodic asthma, and records its use for whooping cough, croup, bronchitis, pleurisy and chronic cough. It was also given as a relaxant for muscle spasm and convulsions, and in small doses for indigestion ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

The Eclectics valued it as an emetic, given in small repeated doses until nausea set in and then pushed to vomiting. King’s warns that heat destroys lobeline, so a decoction or hot infusion was considered irrational ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

In rats trained to self-administer intravenous methamphetamine, a single dose of lobeline (0.3–3.0 mg/kg) reduced responding for both the drug and sucrose. With repeated dosing, tolerance developed to the effect on sucrose, but the reduction in methamphetamine taking persisted, and raising the methamphetamine dose did not overcome it ^{3Reference 3Harrod et al. · 2001AnimalLobeline attenuates d-methamphetamine self-administration in rats — animal modelView study →}.

Lobeline binds the tetrabenazine site on the vesicular monoamine transporter (VMAT2) and blocks dopamine uptake into synaptic vesicles ^{5Reference 5Teng et al. · 1998In vitroLobeline displaces [3H]dihydrotetrabenazine binding and releases [3H]dopamine from rat striatal synaptic vesicles — in vitroView study →}. This, rather than an action on nicotinic receptors, is now regarded as its main mechanism. Lobeline blocked amphetamine-induced dopamine release, hyperactivity and self-administration, and rats did not self-administer lobeline itself ^{4Reference 4Dwoskin et al. · 2002ReviewA novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse — reviewView study →}.

Lobeline did not change methamphetamine-induced dopamine release in the rat striatum. It did lessen the fall in VMAT2 and the long-term loss of striatal dopamine and serotonin, partly by blunting methamphetamine’s rise in body temperature and partly independently of it ^{6Reference 6Eyerman et al. · 2005AnimalLobeline attenuates methamphetamine-induced changes in vesicular monoamine transporter 2 and monoamine depletions in the striatum — ratView study →}.

In microdialysis of the nucleus accumbens, lobeline did not alter methamphetamine’s effect on dopamine, but it prolonged the fall in its metabolite DOPAC ^{7Reference 7Meyer et al. · 2013AnimalEffects of VMAT2 inhibitors lobeline and GZ-793A on methamphetamine-induced dopamine release in vivo — rat microdialysisView study →}.

Gap: Entirely preclinical. No human study has tested lobeline for stimulant-use disorder.

In 14 anaesthetised cats, lobeline injected into the lingual arteries increased the activity of the phrenic, hypoglossal and recurrent laryngeal nerves, with the largest effect on the hypoglossal nerve. The effect disappeared once the vagus and carotid sinus nerves were cut, which places it at the peripheral chemoreceptors ^{17Reference 17van Lunteren et al. · 1984AnimalEffects of dopamine, isoproterenol, and lobeline on cranial and phrenic motoneurons — in vivo (cat)View study →}.

Lobeline has also been used to probe lung chemoreflexes in human breathing studies ^{18Reference 18Jain et al. · 1972Search for evidence of lung chemoreflexes in man: respiratory and circulatory effects of phenyldiguanide and lobeline — human physiologyView study →}.

In anaesthetised rats, lobeline injections containing 36.9% of the trans isomer had a 50.2% weaker effect on breathing than cis-lobeline. Heat and pH drive the one-way conversion from cis to trans ^{20Reference 20Xu et al. · 2022AnimalFrom cis-lobeline to trans-lobeline: study on the pharmacodynamics and isomerization factors — rat respiratory modelView study →}. Lobeline injection has been used as a first-aid respiratory stimulant, now largely displaced by ventilators ^{20Reference 20Xu et al. · 2022AnimalFrom cis-lobeline to trans-lobeline: study on the pharmacodynamics and isomerization factors — rat respiratory modelView study →}.

At high doses the picture reverses. King’s American Dispensatory states that death from lobeline results from respiratory paralysis ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Gap: No controlled clinical trial in any respiratory disease. The data are decades-old physiology.

A set of mouse studies from one research group reports that lobeline reduces depression-like behaviour.

In mice under six weeks of chronic unpredictable stress, lobeline (1 mg/kg) reduced immobility in the forced-swim test and prevented the stress-induced fall in hippocampal BDNF and cell proliferation ^{8Reference 8Roni et al. · 2015AnimalThe effects of lobeline on depression-like behavior and hippocampal cell proliferation following chronic stress in mice — animal modelView study →}.

During nicotine withdrawal, lobeline reduced forced-swim immobility and lessened the rise in noradrenaline in the prefrontal cortex and hippocampus ^{9Reference 9Roni et al. · 2014AnimalThe effects of lobeline on nicotine withdrawal-induced depression-like behavior in mice — animal modelView study →}. After chronic alcohol, it reduced immobility at 24 hours and 14 days of abstinence and reversed the fall in hippocampal serotonin ^{10Reference 10Roni et al. · 2017AnimalLobeline attenuates ethanol abstinence-induced depression-like behavior in mice — animal modelView study →}.

The authors attribute the effects to nicotinic-receptor signalling feeding into monoamine and BDNF pathways ^{8,9,10Reference 8Roni et al. · 2015AnimalThe effects of lobeline on depression-like behavior and hippocampal cell proliferation following chronic stress in mice — animal modelView study →Reference 9Roni et al. · 2014AnimalThe effects of lobeline on nicotine withdrawal-induced depression-like behavior in mice — animal modelView study →Reference 10Roni et al. · 2017AnimalLobeline attenuates ethanol abstinence-induced depression-like behavior in mice — animal modelView study →}.

Gap: No human data. The work comes largely from one laboratory, and forced-swim immobility is a screening test, not clinical depression.

In rats, lobeline given after training improved retention in a passive-avoidance task, and given before training it improved the performance of rats with septal lesions in a spatial water maze. The effective dose in the avoidance task was about 10 times higher than that reported for nicotine; in the water maze the two were similar ^{12Reference 12Decker et al. · 1993AnimalEffects of lobeline, a nicotinic receptor agonist, on learning and memory — ratView study →}.

The one human study was a laboratory proof-of-concept in nine adults with ADHD, given sublingual lobeline at 7.5, 15 or 30 mg. It suggested a modest improvement in working memory, with no significant effect on attention, and lobeline caused mild nausea ^{11Reference 11Martin et al. · 2018Lobeline effects on cognitive performance in adult ADHD — human proof-of-concept studyView study →}.

Gap: A single nine-person study with a working-memory-only effect, and no adequately powered trial.

In mice with pilocarpine-induced seizures, lobeline lengthened the time to the first seizure and reduced the share of animals that seized, much as diazepam did. It also reduced seizure-related DNA damage in the hippocampus and cortex and brought hippocampal catalase activity back to normal ^{13Reference 13da Costa e Silva et al. · 2018AnimalDNA damage and oxidative stress induced by seizures are decreased by anticonvulsant and neuroprotective effects of lobeline — mouse modelView study →}.

This is a single study in one seizure model, without replication, and nothing shows the whole herb reproduces it.

In drug-resistant tumour cells, lobeline inhibited P-glycoprotein-mediated efflux and re-sensitised doxorubicin-resistant cells at non-toxic concentrations. It did not block the BCRP transporter ^{14Reference 14Ma et al. · 2008In vitroLobeline, a piperidine alkaloid from Lobelia, can reverse P-gp dependent multidrug resistance in tumor cells — in vitroView study →}.

In doxorubicin-resistant MCF-7 breast-cancer cells, lobeline cut the IC₅₀ of doxorubicin from 44.8 to 16.7 mg/L. At 20 µmol/L its reversal effect was 71.6% of that of verapamil ^{15Reference 15Chen et al. · 2009In vitroReversal effect and mechanism of lobeline on the multidrug-resistance of human breast cancer cells MCF-7/ADM — in vitroView study →}.

Both are cell-line studies, with no animal tumour model. P-glycoprotein inhibition also points to a possible drug interaction.

A computational search for targets identified lobeline as a cholinesterase inhibitor, because it resembles donepezil in structure. In silico, in vitro and biophysical assays confirmed that it inhibits acetylcholinesterase, with higher affinity than for butyrylcholinesterase. In rat cortical neurons it also protected against glutamate damage by blocking NMDA receptors ^{16Reference 16Remya et al. · 2023In vitroLobeline: a multifunctional alkaloid modulates cholinergic and glutamatergic activities — in silico and in vitroView study →}.

These are enzyme and cell findings on isolated lobeline, with no data in whole animals.

Because lobeline was considered a partial nicotine agonist, it was sold in a range of stop-smoking products ^{2Reference 2Stead et al. · 2012Systematic reviewLobeline for smoking cessation — systematic review (Cochrane)View study →}. A multicentre, double-blind, placebo-controlled Phase 3 trial randomised 750 smokers to sublingual lobeline sulfate or placebo and found no benefit (P=0.62) ^{1Reference 1Glover et al. · 2010RCTA multicenter phase 3 trial of lobeline sulfate for smoking cessation — randomised, double-blind, placebo-controlled trialView study →}.

A Cochrane review found no trial with long-term follow-up, and noted that the one large trial found no effect even on short-term abstinence ^{2Reference 2Stead et al. · 2012Systematic reviewLobeline for smoking cessation — systematic review (Cochrane)View study →}.

Lobeline acts as an antagonist at α4β2 and α3β2 nicotinic receptors and works mainly through VMAT2, so it does not substitute for nicotine ^{4,19Reference 4Dwoskin et al. · 2002ReviewA novel mechanism of action and potential use for lobeline as a treatment for psychostimulant abuse — reviewView study →Reference 19Arias et al. · 2015In vitroFunctional and structural interaction of (-)-lobeline with human α4β2 and α4β4 nicotinic acetylcholine receptor subtypes — in vitroView study →}. It did not help people stop smoking.

Overdose. Excess doses cause nausea and violent vomiting, sweating, dizziness, tremor, a rapid then weak pulse and falling blood pressure. Very high doses can produce respiratory depression, convulsions and collapse. All parts of the plant are poisonous in large amounts, and reported symptoms include vomiting, diarrhoea, salivation, exhaustion and weakness, dilated pupils, convulsions and coma ^{23Reference 23Lady Bird Johnson Wildflower CenterLady Bird Johnson Wildflower Center. (n.d.). Lobelia inflata (Indian tobacco) — plant database entry. Native Plant Information Network, University of Texas at Austin. https://www.wildflower.org/plants/result.php?id_plant=LOINView study →}. Death from lobeline is attributed to respiratory paralysis ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Vomiting as a warning sign. Vomiting was an intended effect in Thomsonian and Eclectic practice, and it is also the first sign of too high a dose ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Heart disease. Lobeline’s nicotine-like effects on heart rate and blood pressure make lobelia unsuitable for people with heart disease. Large doses weaken the circulation ^{21Reference 21Felter et al. · 1898Lobelia (UView study →}.

Who should avoid it. Avoid in pregnancy, in children and in people with heart disease. It is used only in small, carefully measured doses, ideally under an experienced practitioner.

Drug interactions. These have barely been studied. In cell studies, lobeline inhibits P-glycoprotein-mediated drug efflux ^{14,15Reference 14Ma et al. · 2008In vitroLobeline, a piperidine alkaloid from Lobelia, can reverse P-gp dependent multidrug resistance in tumor cells — in vitroView study →Reference 15Chen et al. · 2009In vitroReversal effect and mechanism of lobeline on the multidrug-resistance of human breast cancer cells MCF-7/ADM — in vitroView study →}, so it could in theory alter the handling of drugs carried by that pump. This has not been shown in people, and no CYP450 interaction has been assessed.