Jacques le Houezec | 12 January 2014
Nicotine is the major alkaloid found in tobacco, but it can be found in lower concentrations in plants of the same family, potatoes, tomatoes or eggplants. Humans have always been curious to find plants that can have pleasurable or medicinal effects. Tobacco has been used in South America from pre-Colombian times to the present for magico-religious, medicinal and recreational purposes.
Ritual tobacco use in shamanism is probably as old as the beginning of horticulture, some 8000 years ago. American Indians recognised tobacco (nicotine) as a powerful insecticide for seed protection, and as human vermifuge. Shamans used large amounts of nicotine to induce acute nicotine intoxication, resulting in catatonic states representing symbolic death. Because shamans developed high tolerance to nicotine effects, and because nicotine is quickly eliminated from the body (with a two hours half-life), they returned “miraculously” to life after a few hours (1).
It appears that shamans were exploiting the fact that large doses of nicotine can be ingested without fatality (up to 1500 mg in a recent suicide case report), contrary to the assumptions often reported in many publications, that 30-60 mg of nicotine is a lethal dose in adults (2).
Over the centuries, tobacco use became common in most parts of the world. The ability of nicotine to regulate mood and improve cognitive functioning, and acting as a strong reinforcer of tobacco dependence, is probably the motivation for its widespread use. The most effective way of delivering nicotine to the brain (where most effects occur) is by smoking tobacco, particularly because smokers can modify their nicotine intake on a puff-by-puff basis (called self-titration of nicotine). Smokers can control their nicotine intake to obtain a desired effect, such as stimulation (with low doses) or sedation (with larger doses). Nicotine is then a very suitable drug by which you can get the effect you need at the time you need it, because inhalation with tobacco smoke (or now with e-cigarette vapour) brings nicotine to the brain very quickly (actually faster than an intravenous injection).
Nicotinic receptors that bind nicotine and produce its effects are ubiquitous (they are present in almost all parts of the body), and there are several forms of nicotinic receptors, each with specific localisation and function. Research on the diversity of central nicotinic cholinergic receptors illustrates the complexity of the effects that nicotine has on different neurotransmitters in the brain (3). Consequently, nicotine has been shown to have positive effects on some medical conditions.
The effects of nicotine on Alzheimer's disease are controversial, but it has been shown that patients with Alzheimer’s present large reductions of nicotinic receptors in both the neocortex and hippocampus compared with healthy people. The positive effects of nicotine on cognitive function suggests that nicotinic receptors may contribute to normal cognitive functioning, and that patients with Alzheimer’s disease may benefit from nicotine therapy.
Similarly, epidemiological studies have clearly demonstrated that smoking protects from Parkinson's disease, with an odds ratio of about 0.5 for smokers compared to non-smokers. This is due to the effects of nicotine on dopamine neurons (Parkinson’s disease is caused by the increasing loss of these neurons), both by stimulating motor function, and protecting the neurons from dying. Several studies have failed to show a therapeutic effect of nicotine on Parkinson’s, but those studies used low doses of nicotine, particularly because patients with Parkinson’s disease are often non-smokers. However, in a pilot study on 6 patients (all non-smokers) high doses of nicotine delivered by patches (up to 105 mg/day) over 17 weeks showed a clear improvement of their motor function while their dopaminergic treatment (L-Dopa) was reduced. The most frequent side effects were nausea and vomiting (in 4 out of 6 patients), but these were well controlled with anti-emetic drugs. Unfortunately, no pharmaceutical company has been interested in funding a placebo-controlled trial to confirm this positive effect (4).
Gilles de la Tourette's syndrome is a genetic disorder resulting from basal ganglia abnormality that is typically treated with dopaminergic antagonists, such as the antipsychotic drug haloperidol. Animal studies have suggested that the use of nicotine could have beneficial effects in patients with Tourette’s. Again, a few uncontrolled small studies have shown that a short nicotine treatment improved the clinical signs of Tourette’s patients, but no interest has emerged from the pharmaceutical industry to explore this positive effect of nicotine (5).
In psychiatric patients, nicotine use could be viewed as a self-medication. This is the case in depression and schizophrenia. There is considerable evidence that tobacco smoking and depression are linked. As in all psychiatric conditions, smoking prevalence is higher in depressed patients than in the general population. In depression, this might not be due solely to the effects of nicotine, as it has been shown that tobacco smoke contains substances with antidepressant effects (monoamine oxidases or MAO), but again some small studies have indicated a possible positive effect of nicotine treatment (6). Schizophrenia is also a condition where smoking prevalence is very high (>80%). The psycho-stimulant effects of nicotine might help schizophrenia patients compensate for their cognitive deficits, particularly attentional processes, which have been shown to normalised when schizophrenia patients smoke (7). Schizophrenia patients may also use nicotine to cope with their mood disturbances, like anhedonia, or more generally to ameliorate their negative symptoms (apathy, lack of motivation), or to lessen the side effects of neuroleptics (anti-Parkinsonian effects) that are known to induce extrapyramidal symptoms (restlessness or akathisia). A positive effect of nicotine patches on these symptoms has been demonstrated in non-smokers treated with neuroleptics for psychotic disorders (8).
All these positive aspects of nicotine use have been reviewed 15 years ago (9), but little progress has been made to explore further these potential beneficial effects of nicotine. Renewed interest in nicotine science, linked with the recent development of e-cigarettes, might inspire new investigations into the positive effects of nicotine including its potential role in disease prevention and treatment.
- Le Houezec J, Benowitz NL. Basic and clinical psychopharmacology of nicotine. Clin Chest Med. 1991;12:681-699.
- Mayer B. How much nicotine kills a human? Tracing back the generally accepted lethal dose to dubious self-experiments in the nineteenth century. Arch Toxicol. 2014 Jan;88(1):5-7.
- Deneris ES, Connolly J, Rogers SW, Duvoisin R. Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors. Trends Pharmacol Sci. 1991;12:34-40.
- Villafane G, Cesaro P, Rialland A, Baloul S, Azimi S, Bourdet C, Le Houezec J, Macquin-Mavier I, Maison P. Chronic high dose transdermal nicotine in Parkinson's disease: an open trial. Eur J Neurol. 2007;14:1313-1316.
- Sanberg PR, Silver AA, Shytle RD, Philipp MK, Cahill DW, Fogelson HM, et al. Nicotine for the treatment of Tourette's syndrome. Pharmacol Ther 1997;74:21-5.
- McClernon FJ, Hiott FB, Westman EC, Rose JE, Levin ED. Transdermal nicotine attenuates depression symptoms in nonsmokers: a double-blind, placebo-controlled trial. Psychopharmacology (Berl). 2006 Nov;189(1):125-33.
- Ward PB, Hoffer LD, Liebert BJ, Catts SV, O'Donnell M, Adler LE. Replication of a P50 auditory gating deficit in Australian patients with schizophrenia. Psychiatry Res. 1996;64:121-35.
- Koshe Anfang M, Pope HG Jr. Treatment of neuroleptic-induced akathisia with nicotine patches. Psychopharmacology. 1997;134:153-6.
- Le Houezec J. Nicotine: abused substance and therapeutic agent. J Psychiatry Neurosci. 1998;23:95-108.