Nicotine Therapy for Neuropsychiatric Disorders
Nicotine Therapy for Neuropsychiatric Disorders
June 1998; Volume 1: 67-70
By Mady Hornig, MD
Smoking, one of the leading preventable causes of death in the United States, is clearly associated with major adverse health effects. The specific health risks attributable to nicotine itself, however, have not been fully determined. Nicotine is a potent and addictive component of tobacco. When delivered in safer forms than through hot cigar and cigarette smoke, nicotine may also produce beneficial effects, including cognitive enhancement, improved tic control, prevention of Alzheimer’s and Parkinson’s disease, and antidepressant efficacy.
History
Although tobacco has been used worldwide for centuries, the specific application of nicotine to the treatment of disease states is relatively new. Concern about nicotine’s addictive potential and the health risks associated with tobacco use have limited the development of nicotine as a therapeutic agent.
Culture
Cultural influences play a major role in the acceptability of smoking and other forms of tobacco use (e.g., chewing) in different settings. Smoking bans, enforced by federal, state, or local ordinances, have spread throughout the United States. This cultural climate has heightened the disdain for use of any substances associated with tobacco, including nicotine.
Despite these barriers, evidence to support the therapeutic efficacy of agents that stimulate nicotinic pathways has grown. To avoid the negative connotations of a substance of abuse, researchers have renamed the class of agents that modulate nicotinic and muscarininc systems as "cholinergic channel activators."
Pharmacokinetics
The pharmacokinetics vary slightly with the method of administration: transdermal delivery system, chewing gum, or nasal administration. The peak plasma concentration (Cmax) of nicotine following 15-60 mg nicotine patch administration is proportional to the dose and in the same range for both smokers and nonsmokers. Mean delivered dose of nicotine is higher with the Nicoderm® system than with the Habitrol system. Levels reported with chewing gum are comparable.
Venous plasma concentrations of nicotine following single dose administration of nasal spray range from 5-12 mcg/L (similar to those attained with the lower 2 mg and 4 mg gum dosages), but, with ad libitum administration, steady-state concentrations ranging from 16-29 mcg/L have been achieved. Time to peak plasma concentration (tmax ) following 1 mg dose intranasally is 11-13 minutes. This is faster than with other nicotine delivery systems, but considerably slower than that seen with cigarette smoking.
Mechanism of Action
The actions of nicotine include both direct and indirect effects on multiple neurotransmitter systems. Nicotine acts directly on a family of nicotinic receptor subtypes of acetylcholine (ACh) receptors that are incompletely characterized. Complex interactions with dopaminergic tracts, which likely vary for subcortical and cortical brain regions, have been observed.
Clinical Studies
Although nicotine products are officially indicated for use in smoking cessation, studies in a variety of neuropsychiatric conditions, including depression and schizophrenia, have been performed. Identified psychiatric patients, particularly those with depressive and anxiety disorders, have a higher rate of smoking.1
Mood Disorders. The presence of depressive symptoms is associated with difficulties maintaining abstinence from smoking.2 Nondepressed patients with a history of major depressive disorder (MDD) have an increased rate of depressive relapse during smoking cessation when compared to patients without a history of MDD.3-5 The three-month incidence of new MDD episodes during smoking cessation increased from 2% in patients without a history of MDD to 17% and 30% in patients with histories of either single or recurrent episodes of MDD, respectively.4
Nicotine patch therapy appears more effective than nicotine gum in these patients.6 Transdermal nicotine patches have been associated with increased REM sleep and short-term mood elevation in nonsmoking depressed subjects.7 Healthy volunteers experienced increased sleep fragmentation and decreased REM sleep with nicotine patch administration.7
Alzheimer’s and Other Dementias. There is evidence of an inverse association between smoking and development of Alzheimer’s disease.8 In addition, trials of nicotine patch administration in patients with already existing Alzheimer’s disease indicate improvement in semantic memory.9-11
Parkinson’s. As with Alzheimer’s, smokers are significantly less likely to develop Parkinson’s disease,12 an effect that does not appear secondary to selective mortality.13 No controlled studies of nicotine efficacy in patients with Parkinson’s disease could be found, although such clinical application is of great theoretical as well as practical interest.
Substance Abuse. Nicotine dependence occurs at high rates in cocaine-abusing populations; it has been suggested that interactions of nicotine with dopamine/reward system functioning may play a role in modulating cocaine craving. As with Parkinson’s disease, there is substantial theoretical and practical interest in controlled trials assessing the efficacy of cholinergic channel activators, including nicotine, as therapeutic tools in patients with psychostimulant abuse, including cocaine.
Attention Deficit/Hyperactivity Disorder (AD/HD). The nicotine system is closely linked to attentional systems, and the clinical manifestations of AD/HD and other disorders of attention are likely modulated by nicotine administration. AD/HD is associated not only with in utero exposure to nicotine dependence; in male rats exposed prenatally to nicotine, hyperactivity is associated with a significant increase in cortical nicotinic receptor densities. However, binding affinity of nicotine does not change.
Nicotine is thought to enhance cognitive functioning by screening irrelevant stimuli from the subject’s awareness, acting as a stimulus filter, and increasing the capacity of the subject to process perceptual stimuli.14 These cognitive-enhancing effects may be of potential benefit not only to patients with AD/HD, but may play a role in the attentional improvements seen in patients with Alzheimer’s disease with nicotine administration. Lastly, transdermal nicotine has been shown effective in patients with AD/HD who are either nonsmokers or abstinent smokers.15
Other medical applications. Smoking is inversely related to the risk of endometriosis, uterine fibroids, and endometrial cancer. Control of recurrent aphthous ulcers, ulcerative colitis, and body weight may also be benefits of smoking.16
Adverse Effects
Nicotine preparations are typically well-tolerated. Side effects specific to the transdermal delivery system may include irritation at the patch site. Common, general side effects of exogenous nicotine administration include gastrointestinal upset and overstimulation.
Drug Interactions
Drug interactions have been noted with several different medications. Among the more concerning drug interactions, vasopressin appears to have a synergistic interaction with nicotine, with the potential to cause hypotension and bradycardia.17 Other drug interactions may actually enhance the therapeutic aspects of nicotine or the coadministered agent. With haloperidol/nicotine coadministration, for example, improvement in control of symptoms of Tourette’s syndrome18 and of cognitive function in schizophrenics19 has been observed.
Formulation
Although nicotine is found in high concentration in tobacco products, the risks of lung and oral cancers and respiratory tract illnesses are such that smoking or chewing tobacco cannot be condoned. Nicotine is widely available in alternative forms, including transdermal patch, chewing gum, and the newly developed nasal spray. Agonists of nicotinic and other ACh receptors, now dubbed the "cholinergic channel activators," are also in development.
Dosage
Dosages of the nicotine patches range from 7-60 mg, and the nicotine chewing gum ranges from 2-4 mg. There is limited specific information regarding the application of nicotine preparations for conditions other than smoking cessation. Thus, further controlled studies of nicotine administration at different doses in specific disorders will be needed before dosing recommendations can be made.
Conclusion
The therapeutic potential of nicotine and other cholinergic channel activators is vast, and ranges from neuropsychiatric indications to disturbances of the immune/inflammatory system. The short-term safety and tolerability of nicotine preparations (other than tobacco) appears to be high. Much research will be required to establish the mechanism of action, therapeutic range, and long-term safety of these potent agents. However, individuals with disorders such as Alzheimer’s disease, attention deficit/hyperactivity disorder, and affective illnesses who are resistant or refractory to standard treatments may benefit from a cautious, "off label" trial.
References
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6. Hall SM, et al. Mood management and nicotine gum in smoking treatment: A therapeutic contact and placebo-controlled study. J Consulting Clin Psychol 1996;64:1003-1009.
7. Salin-Pascual RJ, et al. Effects of transdermal nicotine on mood and sleep in nonsmoking major depressed patients. Psychopharmacol 1995;121: 476-479.
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9. Parks RW, et al. Increased regional cerebral glucose metabolism and semantic memory performance in Alzheimer’s disease: A pilot double blind transdermal nicotine positron emission tomography study. Neuropsychol Rev 1996;6:61-79.
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11. Wilson AL, et al. Nicotine patches in Alzheimer’s disease: Pilot study on learning, memory, and safety. Pharmacol Biochem Behav 1995;51:509-514.
12. Hellenbrand W, et al. Smoking and Parkinson’s disease: A case-control study in Germany. Int J Epidemiol 1997;26:328-339.
13. Morens DM, et al. Evidence against the operation of selective mortality in explaining the association between cigarette smoking and reduced occurrence of idiopathic Parkinson disease. Am J Epidemiol 1996;144:400-404.
14. Kassel JD. Smoking and attention: A review and reformulation of the stimulus-filter hypothesis. Clin Psychol Rev 1997;17:451-478.
15. Levin ED, et al. Nicotine effects on adults with attention-deficit/hyperactivity disorder. Psychopharmacol 1996;123:55-63.
16. Baron JA. Beneficial effects of nicotine and cigarette smoking: the real, the possible and the spurious. Brit Med Bull 1996;52:58-73.
17. Groudine SB, Morley JN. Recent problems with paracervical vasopressin: A possible synergistic reaction with nicotine. Med Hypotheses 1996;47:19-21.
18. Silver AA, et al. Case study: Long-term potentiation of neuroleptics with transdermal nicotine in Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 1996;35:1631-1636.
19. Levin ED, et al. Nicotine-haloperidol interactions and cognitive performance in schizophrenics. Neuropsychopharmacol 1996;15:429-436.
June 1998; Volume 1: 67-70
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