ARTICLE IN BRIEF

COULD A TRANSDERMAL NICOTINE PATCH be neuroprotective, investigators are asking?

A new randomized, placebo-controlled study found “significant nicotine-associated improvements in attention, memory, and psychomotor speed,” with excellent safety and tolerability in patients with amnestic mild cognitive impairment. The story looks at this and other recent data suggesting that transdermal nicotine could be neuroprotective for neurological disorders.

Dyskinesia and impulsivity in Parkinson disease, cognitive defects in attention deficit-hyperactivity disorder (ADHD), and now attention and memory in mild cognitive impairment (MCI): the list of reported neurological benefits just keeps growing in animal and human studies of nicotine.

The latest study, published in the Jan. 10 Neurology, involved 67 subjects with amnestic MCI randomized for six months to either placebo or 15 mg per day of transdermal nicotine. The results found “significant nicotine-associated improvements in attention, memory, and psychomotor speed,” with excellent safety and tolerability.

“The idea that nicotine would have positive therapeutic effects on brain function is still a novel idea to a lot of people,” said the senior author of the paper, Paul Newhouse, MD, professor of psychiatry, pharmacology and medicine, and director of the Center for Cognitive Medicine at Vanderbilt University School of Medicine in Nashville.

“Nicotine obviously carries a lot of baggage,” he told Neurology Today, “but this paper is based on work we started doing in the late 1980s on the beneficial effects of nicotine in Alzheimer disease. There are now clinical trials of nicotine in Parkinson disease. What we're trying to discover is the range of benefits.”

Dr. Newhouse has previously published studies showing that nicotine improves cognitive defects in young adults with ADHD.

DR. PAUL NEWHOUSE: “The idea that nicotine would have positive therapeutic effects on brain function is still a novel idea to a lot of people. Nicotine obviously carries a lot of baggage, but this paper is based on work we started doing in the late 1980s on the beneficial effects of nicotine in Alzheimer disease. There are now clinical trials of nicotine in Parkinson disease. What were trying to discover is the range of benefits.”

“Nicotinic receptors in the brain appear to work by regulating other receptor systems, like a gain amplifier,” he said. “If you're sleepy, it tends to make you more alert. If you're anxious, it tends to calm you. Obviously the results of small studies often aren't replicated in larger studies, but at least nicotine certainly looks safe. And we've seen absolutely no withdrawal symptoms. There doesn't seem to be any abuse liability whatsoever in taking nicotine by patch in non-smokers. That's reassuring.”

On the primary outcome variable in his MCI study, the Conners' Continuous Performance Test — a task-oriented computerized assessment of attention disorders and neurological functioning — Dr. Newhouse and colleagues found a significant improvement among the 34 subjects who were randomized to nicotine and completed the study, compared with the 33 completers randomized to placebo (p=0.031). Significant nicotine-associated improvements were also seen in computerized tests of attention, memory and psychomotor speed, and in patient/informant ratings of cognitive impairment.

DR. MARYKA QUIK: “Parkinson disease researchers look at this literature skeptically, mostly because nicotine is associated with smoking. But there is a huge literature showing that smoking protects against Parkinson disease, and we know there are nicotinic receptors throughout the brain. My attitude has been: lets test to see what happens.”

The only measure on which no statistically significant benefit was seen was clinician-rated global improvement. But according to Dr. Newhouse, “We were never powered sufficiently for the global impression rating.”

The potential for nicotine has been borne out in other recent trials. At the University of Vermont College of Medicine, a small, randomized 12-week trial is now underway testing whether nicotine can reduce impulsivity in people with Parkinson disease.

“Nicotine has been associated with a reduction in impulsivity in ADHD,” said the study's principal investigator, James Boyd, MD, assistant professor of neurology. “It could hypothetically normalize decision-making.”

In early 2012, the German and US Parkinson Study Groups will collaborate to conduct a multi-center phase 2 trial investigating the potential disease-modifying effects of transdermal nicotine in early Parkinson disease, Dr. Boyd said.

RELIEF OF INVOLUNTARY MOVEMENTS

At the November annual meeting of the Society for Neuroscience in Washington, DC, three abstracts were presented by a basic scientist who has devoted much of her career to understanding the effects of nicotine, Maryka Quik, PhD, director of the Neurodegenerative Diseases Program at SRI International, an independent, nonprofit research institution formerly associated with Stanford University and based in Menlo Park, CA.

Dr. Quik described rodent studies at the meeting showing that nicotine may relieve both levodopa-induced abnormal involuntary movements, and tardive dyskinesias associated with neuroleptic use. In 2007, in Annals of Neurology, she reported similar benefits of nicotine in monkeys, and has published some three dozen other studies on the drug in the past nine years.

“Parkinson disease researchers look at this literature skeptically, mostly because nicotine is associated with smoking,” Dr. Quik told Neurology Today. “But there is a huge literature showing that smoking protects against Parkinson disease, and we know there are nicotinic receptors throughout the brain. My attitude has been: let's test to see what happens.”

The NINDS program director for Parkinson disease research acknowledged that inklings of nicotine's potential role as neuroprotective agent have been seen for years.

“It may be a long haul, but there is a sense of excitement about these studies,” said Beth-Anne Sieber, PhD. “Epidemiologic studies have suggested for many years that people who smoke are less likely to develop Parkinson disease. The extrapolation is that it may be neuroprotective. What Maryka Quik is trying to do is identify the receptors in the brain that actually may be connected to improving or correcting levodopa-associated dyskinesia. She's using a pretty powerful array of molecular tools in animal models. She's trying to pinpoint which nicotinic receptor subtypes are the most useful targets.”

But according to Dr. Newhouse, nicotine itself — not any of the subtypes now being studied and even developed into drugs by biotech companies — might yet prove to the most effective neuroprotective agent.

“Nicotine has the advantage that it is kind of a dirty drug, it covers all types of nicotine receptors,” he said. “The selective agents that the pharmaceutical industry is studying may miss some subtypes that are important. That's the puzzle: we haven't yet figured out which subtypes matter most.”

As to whether clinical neurologists should consider suggesting the use of a low-dose nicotine patch to their patients with MCI or Parkinson disease, both Dr. Newhouse and Dr. Boyd were cautious.

“I can't officially recommend that,” Dr. Newhouse said. “It looks safe. It looks reasonable. But the long-term clinical impact still has to be better assessed. I think it's still a little premature. But certainly the published data suggest it has potential benefits for MCI and it definitely appears to be a reasonable strategy for further testing.”