Although the evidence linking cigarette smoking to lung cancer is overwhelming, one has to give the devil his due: Nicotine, the main pharmacologically active ingredient of tobacco, may possibly lead to some helpful new drugs for Alzheimer’s disease and schizophrenia, as well as several other neuropsychiatric diseases.

Some of the latest information on this provocative subject was presented at the annual meeting of the American Association for the Advancement of Science, held last month in Washington, D.C.

Alzheimer’s disease is characterized by degeneration of various structures in the brain, with development of amyloid plaques and neurofibrillary tangles. But deficiencies in the neurotransmitter acetylcholine also occur, and acetylcholine is known to be crucial for attention, learning, and memory—areas where patients with Alzheimer’s have serious problems. In fact, the only two drugs currently available to help such patients are associated with modest improvements in cognitive function block the breakdown of acetylcholine in the brain.

Now enter nicotine. In the brain, some of the nerve receptors that control the release of acetylcholine are stimulated by nicotine. They are called nicotinic cholinergic receptors. A good 50 percent of these receptors are known to be lost in the brains of patients with Alzheimer’s, but that putatively leaves some 50 percent. Thus investigators reckoned that if nicotine, or a nicotinelike compound, was given as a drug to a patient with Alzheimer’s, it might act on the intact nicotinic cholinergic receptors in the brain, step up the release of acetylcholine, and in turn boost attention, learning, and memory.

Evidence suggests that such reasoning has some merit. For example, Paul Newhouse, M.D., a psychiatrist with the University of Vermont College of Medicine in Burlington, and his colleagues first showed, in human subjects, that nicotinic cholinergic receptors are important for learning and memory. More recently they have found, in seven patients with Alzheimer’s, that a novel nicotinelike compound called ABT-418, made by Abbott Laboratories, can improve learning and memory significantly, at least over the short term.

Then Edward D. Levin, Ph.D., of Duke University Medical Center in Durham, N.C., with gerontology colleague Heidi White, did an eight-week study with eight patients with Alzheimer’s. The patients received a nicotine patch for four weeks, then a placebo for four weeks. The nicotine patch led to improved attentiveness, and the patients tolerated the patch well.

Some promising nicotine-related compounds for Alzheimer’s are also emerging from SIBIA Neurosciences Inc., in La Jolla, Calif., which was recently bought by Merck. G. Kenneth Lloyd, Ph.D., a pharmacologist with Scripps Research Institute in La Jolla, was until recently with SIBIA and did some animal research that underscored the potential of the compounds. Although he could not give out details about the drugs, "the preclinical profiles are very promising," he said.

As for schizophrenia, the neurotransmitter scenario is more complex than in Alzheimer’s. Dopamine and acetylcholine are involved. The best drugs currently available for schizophrenia—antipsychotics and neuroleptics—influence dopamine. But drugs that act on the nicotinic cholinergic receptors might also prove of benefit to patients with schizophrenia, researchers speculated, since acetylcholine plays a role in attention, and individuals with schizophrenia have a problem with attention. Another reason is that nicotinic cholinergic receptors are not just on nerves that make acetylcholine, but on nerves that make other kinds of neurotransmitters as well. Thus, these drugs could pep up the release of those neurotransmitters too, perhaps leading to some favorable clinical changes. And indeed, some encouraging results in the domain of nicotinic cholinergic receptors and schizophrenia are emerging.

For instance, nicotine patches have improved the attention of some individuals with schizophrenia, Levin and coworkers have found. Robert Freedman, M.D., chair of psychiatry at the University of Colorado School of Medicine in Denver, has gotten some encouraging results in experimental animals with a drug developed at the University of Florida that acts on a particular nicotinic cholinergic receptor—the alpha-7 receptor. He hopes to test the drug in some patients with schizophrenia as soon as the Food and Drug Administration gives him the green light.

Researchers at Abbott Laboratories have identified still another nicotinic cholinergic receptor-stimulating compound that might combat schizophrenia. It appears to exert its favorable influence via dopamine, not acetylcholine.

Drugs that interact with the nicotinic cholinergic receptors are also looking auspicious for Tourette’s syndrome and for Parkinson’s disease. Paul Sanberg, Ph.D., a professor and research director of the department of neurosurgery at the University of South Florida College of Medicine, has been doing a lot of research in the former area, and Newhouse in the latter.

Certainly, getting such drugs from the lab to patients will not be without some bumps in the road. For instance, Newhouse offered some caution regarding the development of such drugs for Alzheimer’s: "I think the long-term effects of these drugs need to be established. . . . There is a long leap from acute improvement in learning and memory to long-term clinical benefit, and that has to be done. [Also] the issue of long-term safety has to be dealt with—whether enough of these drugs can be given to produce the desired effect without long-term side effects. . . ."

But all in all, investigators in the field are bullish about the outcome of their efforts. For example, in an interview Lloyd said, "It is a very competitive field, and I am sure that it will be very successful."

Added Levin: Since not just academic researchers but big pharmaceutical companies like Abbott, Merck, and Pfizer are working in this field, "a whole new class of drugs will probably be coming out."

And as Michael Williams, Ph.D., director of neuroscience discovery at Abbott Laboratories near Chicago, asserted: "I have read Bob Freeman’s papers. . . . I think that what Bob is doing is going to revolutionize antipsychotic medications."