Galantamine Twofer: Better memory and resistance to tobacco …

Galantamine Prevents
Smoking Resumption

Perhaps if you’re thinking more clearly, you don’t need tobacco

By Will Block

It’s easy to quit smoking. I’ve done it hundreds of times.
— Mark Twain

A

ccording to the Center for Disease Control and Prevention, in 2010 nearly 20% of adult Americans were smoking tobacco. That represents 43.5 million people! This is astonishing when you consider that tobacco remains the leading cause of preventable death in the United States. Worldwide, cigarette smoking causes more than 5 million deaths annually, which is more than double the number of deaths per year attributed to the greatest mass murderer of all time, Mao Tse-tung. An estimated 65 million Chinese died as a result of Mao’s merciless attempts to create a new “socialist” China. But that took 27 years. At the current smoking death rate, that number would be exceeded in just 13 years.

Smoking Leads to Multiple Diseases and Disorders

Who characterizes the largest subpopulation of smokers in the U.S.? A recent journal article, finds that cigarette smoking is especially common among individuals with psychiatric comorbidity (the presence of one or more diseases and/or disorders, in addition to a primary disease or disorder). This group includes individuals with primary psychiatric disorders and other addictions.1 But that’s not an exhaustive description of everyone who smokes. You don’t have to be crazy if you smoke, but you are crazy if you do.

Nevertheless, while behavioral modification and pharmacologic treatments to stop smoking are available and “effective”—altogether these treatments increase the chances of quitting by two- to three-fold—they are far from satisfactory. The scorching truth is that 70 to 90% of smokers resume smoking within a year of treatment. Even though quitting is associated with immediate health benefits irrespective of age or presence of smoking-related diseases, to date most treatments fail to sustain cessation.

Galantamine’s Multiple Actions

Most of the established drugs that promote smoking cessation target nicotinic acetylcholine receptors (nAChRs). Indeed, all first-line pharmacotherapies for nicotine addiction—including nicotine replacement therapy, bupropion, and varenicline—affect nAChRs. Thus it seems plausible that galantamine, a reversible and competitive acetylcholinesterase inhibitor (AChEI)—which is used in the treatment of Alzheimer’s disease—may be of benefit. That’s because galantamine dramatically sensitizes microglial nAChRs and increases the release of acetylcholine (ACh). Some preclinical and clinical studies support the potential efficacy of AChEIs for smoking cessation, although their effects on the behavioral and physiological responses to nicotine have not been examined.


Tobacco remains the leading cause of
preventable death in the U.S.


Galantamine has been clinically used as a cognitive enhancer in the treatment of dementia and is being tested as a treatment for traumatic brain injury, stimulant addiction, and neuropsychiatric conditions associated with cognitive deficits. Other evidence supports the use of AChEIs for the treatment of nicotine dependence.

Schizophrenic Smoking May Be Reduced

For example, one study investigated the use of galantamine in patients with schizophrenia, a group for whom the rate of cigarette smoking is much higher than in the general population.2 While the results are not completely clear, the author of that study believes that galantamine may be helpful for improving smoking behavior. Because it operates on the same receptors that are affected by nicotine, galantamine may yet be found to serve as a nicotine replacement therapy.

Preliminary findings show that galantamine therapy reduces agitation and improves social and hygienic habits, such as remembering to brush one’s teeth. The author of the above study concluded that there is hope for establishing a therapeutic use for galantamine in patients with refractory schizophrenia.

Alcohol Dependency and Smoking

In another study, researchers investigated whether galantamine reduces smoking by performing a 24-week randomized, placebo-controlled, multicentered clinical trial in recently detoxified alcohol-dependent patients.3 Of 114 randomized smoker-participants, 56 received galantamine and 58 received placebo for 12 weeks. Follow-up examinations were terminated after an additional 12 weeks without treatment. While smoking behavior did not differ between both groups at baseline, after treatment, there were significant differences with a 20% lower cumulative number of smoked cigarettes and a 15% lower number of smoking days in the galantamine group compared to placebo. The average number of smoked cigarettes per smoking day as well as the cotinine (a metabolite of nicotine) values decreased about 10%. Altogether the data indicate that galantamine reduces smoking behavior even without any additional specific intervention.


The scorching truth is that 70 to
90% of smokers resume smoking
within a year of treatment.


Nicotine-Withdrawal Cognitive Impairments Reversed

Galantamine has recently been shown to reverse nicotine withdrawal-induced cognitive impairments in mice.4 This suggests that galantamine may help prevent relapse in human smokers. But, there are no studies examining whether galantamine administration lessens nicotine self-administration and/or reinstatement of nicotine seeking in rodents. So a new study was designed to determine the effects of galantamine on nicotine taking and whether it could prevent the resumption of nicotine-seeking behavior, in an animal model of relapse.4

At the same time, the effects of galantamine on sucrose-maintained responding and sucrose-maintained seeking were also examined to determine whether galantamine’s effects generalized to other reinforced behaviors.

An inverted U-shaped dose-response curve was obtained when animals self-administered different unit doses of nicotine. This means that a low dose and very high dose had the highest response for infusion of nicotine, while an acute galantamine administration lessened nicotine self-administration. Galantamine administration also weakened the reinstatement of nicotine-seeking behavior. No significant effects of galantamine on sucrose self-administration or sucrose reinstatement were noted.

AChEIs have also been shown to produce nausea and vomiting in humans. Nonetheless, at doses required to diminish nicotine self-administration, no effects of galantamine on nausea/malaise were noted. These results indicate that increased acetylcholine levels and nicotinic acetylcholine receptor stimulation are sufficient to offset nicotine taking and seeking in rats, and that these effects are reinforcer selective and not due to adverse malaise symptoms such as nausea.

Galantamine for Smoking Cessation

The goal of a new study done at Yale University’s School of Medicine was designed to investigate galantamine’s actions on multiple outcomes of smoking cessation, including withdrawal severity and cognitive performance, as well as subjective and physiological responses to IV administered nicotine.5

A total of 12 smokers (11 men and 1 woman) participated in a double-blind, placebo-controlled, crossover study. None of these were seeking treatment. The subjects were comprised of African-Americans (n=4), Caucasians (n=5), and Hispanics (n=3). The average age of the smokers was 37.2 years and the average number of cigarettes smoked/day was 15.0. All subjects received a Fagerstrom Test for Nicotine Dependence and the average score was 4.8. (7–10 = highly dependent; 4–6 = moderately dependent). The average baseline plasma cotinine levels were 269 ng/ml (levels over 300 ng/ml are associated with heavy smoking, more than 20 cigarettes/day). No other addictions were reported, and all physical, laboratory, and psychiatric examinations were within normal limits.

Following an adaptation session, smokers had two 4-day treatment periods, assigned in random sequence to either galantamine (8 mg/day) or placebo treatment. Between each treatment period a washout period was scheduled lasting a minimum of 4 days, which was deemed sufficient to minimize carryover effects from galantamine, which has an elimination half-life of 7 hours.

During the treatment periods, for the first 3 days the smoker-subjects had clinic visits twice daily to receive either galantamine or placebo and to complete the outcome measures. Beginning at midnight on day 1, smokers were asked to stop smoking until the morning of day 4. Abstinence from smoking was verified with expired carbon monoxide (CO).

On day 4, smokers began an experimental session. First, smokers had an indwelling catheter inserted into an upper arm vein. After the collection of baseline measures, smokers received an oral dose of either galantamine or placebo. One hour later, when peak plasma levels of galantamine were expected, the subjects received two randomly ordered injections of nicotine, 1 mg nicotine per 70 kg (154 lb) of body weight, or placebo. A second injection was given 60 minutes later to allow sufficient time for the physiological and subjective effects of nicotine to return to baseline levels. From prior work, the researchers knew that this dose of nicotine produces robust physiological and subjective responses.

Measuring the Effects of Galantamine

The researchers assessed biochemical, physiological, subjective, and cognitive domains. Biochemical measures included CO and plasma cotinine levels to verify abstinence from smoking and to assess the amount of nicotine intake, respectively. Plasma cotinine measurements were taken before study participation, and CO levels were obtained daily during each treatment phase.

Other physiological measures included systolic and diastolic blood pressures and heart rate, which were measured daily during medication treatment. Physiological measures were taken in the experimental sessions at 0, 1, 2, 3, 5, 8, 10, 15, 30, and 45 min in relation to saline or nicotine injections.

Smoking Urges, Mood States, and Drug Effects

The subjective measures included the Questionnaire on Smoking Urges-Brief, the Profile of Mood States, and the Drug Effects Questionnaire. In the first test, Smoking Urges, smokers were asked how strongly they agreed or disagreed with items on a 7-point scale. This scale has two factors: 1 reflects an urge to smoke for stimulation, and 2 reflects an urge to smoke to relieve negative mood and withdrawal. This scale has been found to be highly reliable and reflects levels of nicotine deprivation.

Next, the subjects were measured in the Mood State test, of which there were 65 items (rated on a scale from 0, “not at all,” to 4, “very much so,” for the past 24 hours) that make up six subscales: tension-anxiety, depression-dejection, anger-hostility, vigor-activity, fatigue-inertia, and confusion-bewilderment.

The Smoking Urges and Mood State measures were taken daily during each treatment phase, and on the test session, they were administered three times: at the beginning, 1 hour after the medication treatment, and at the end of each experimental session.

The final test on Drug Effects was used to measure acute effects of IV nicotine and consisted of the following items: “feel drug strength,” “feel stimulated,” “like the drug effects,” “good drug effects,” “feel high,” “bad drug effects,” “feel down,” and “feel anxious.” Smokers rated each item on a 100-mm scale, from “not at all” to “extremely.” The Drug Effects Questionaire was given at 1, 3, 5, 8, 10, 15, 30, and 45 minutes after saline or nicotine administration.

Cognitive Performance and Sustained Attention

Then, cognitive performance was assessed with the Sustained Attention to Response Test (SART), a 225-trial Go/No-Go task that assesses the ability to withhold responses to an infrequently occurring target (No-Go trials). Go/No-go tests are used to measure capacity for sustained attention and response control. Reaction times and errors on Go trials were also assessed. The test was administered twice: on day 4 of each treatment period and 1 hour after galantamine or placebo administration. Because the effect of AChEIs on sustained attention may be most pronounced at the end of the task, the Yale researchers examined treatment effects over time.


Galantamine may help prevent
relapse in human smokers.


Study outcomes were analyzed with a mixed-effect, repeated-measures crossover model using a statistical analysis system. Each model included fixed-effect terms for treatment (placebo or galantamine) and time of measurement (day in the study, time since treatment, or trial in task for the SART) as well as the interaction of these two effects.

For many of the measurements, separate analyses were conducted, focusing on the main contrasts of interest—treatment (galantamine vs. placebo), changed saline, and nicotine responses. The measurements were elaborate and lengthy.

Physiological Responses to IV Nicotine

Following nicotine administration, peak heart rate and blood pressure values were reached at 1 minute and returned to baseline in approximately 15 minutes. Galantamine treatment did not change the heart rate or systolic blood pressure responses to IV nicotine. However, galantamine reduced the diastolic blood pressure response to nicotine, while no treatment effects were observed in response to saline for any of the outcomes.

Subjective Responses to IV Nicotine

Following nicotine administration, peak subjective responses were reached at 1 minute and returned close to baseline values within 15 minutes. Galantamine reduced ratings of “stimulated,” “like the drug effects,” “good drug effects,” and “bad effects.”

There were no treatment effects for the rating of “feel drug strength,” “feel high,” “feel down,” or “feel anxious.” There were no treatment effects in response to saline administration. Regarding the Smoking Urges test, no treatment effect was observed for either factor 1 or factor 2.

For the experimental session, galantamine treatment was associated with a lower rating for factor 1 (an urge to smoke for stimulation), but not factor 2 of the Urges test. The average factor 1 scores of the Smoking-Urges Questionnaire were 16.7 at baseline, 16.5 1 hour after medication treatment, and 16.4 at the end of the session under placebo treatment. However, for galantamine, Smoking Urges measurements decreased, with the corresponding values dropping from 17.1 to 16.4 to 15.6, yielding a significant reduction of 0.82. There were no treatment effects on the Mood States. For daily breath CO measurements, there were no significant main effects for treatment or treatment-by-time interaction.

Cognitive Measures

On No-Go trials, the mean error rate was 47.3 % for galantamine, and 38.9 % for placebo. The error rate was significantly lower with galantamine treatment. The error rate on No-Go trials increased over time in the placebo condition, but not for galantamine. On Go trials for galantamine, the mean error rate was 4.5 %, and the mean reaction time was 421.2 ms. This means that galantamine enabled the subjects to more successfully inhibit smoking. In the placebo leg, the mean error rate was 4.6 %, and the mean reaction time was 429.3 ms. There were no significant effects of treatment on Go trials.

Galantamine treatment (8 mg/day for 4 days) lessened some of the subjective responses to nicotine compared to placebo treatment. Furthermore, smokers reported reduced cravings for cigarettes and showed improved performance on the No-Go trials of a Go/No-Go task.

To repeat, galantamine also reduced the increases in diastolic blood pressure induced by IV nicotine. Overall, galantamine treatment was well tolerated by cigarette smokers during the 4-day treatment.

As well, the study reduced some, but not all, of the subjective effects of nicotine, including “like the drug effects,” “good drug effects,” “bad drug effects,” and “stimulated.”

Defeating the Pleasure Associated with Smoking

Whether an individual receives pleasurable effects from cigarettes, before an attempt to quit smoking, have been predictive characteristics of smoking relapse. Thus it is suggested that substances that target the pleasurable effects of smoking may facilitate quitting. It remains to be determined if galantamine also reduces the pleasurable effects of smoking cigarettes.

Lower Craving for Tobacco with Galantamine

Galantamine reduced cigarette cravings in the experimental session without affecting the craving during the first 3 days of treatment. Why this was the case is not clear, but it could be due emergence of galantamine’s effects following several days of treatment.

While the current study did not assess smoking behavior, other studies support the potential effectiveness of AChEIs for smoking cessation. For example, in a clinical trial for alcohol dependence, galantamine treatment reduced smoking behaviors, including cigarettes used per day, as well as cotinine levels in 114 alcohol-dependent smokers.6

The Improvement of Cognition and Cessation

Conceivably, galantamine and other AChEIs may facilitate smoking cessation by improving cognitive deficits induced by abstinence. This hypothesis remains to be tested in future studies. Galantamine’s capacity to reduce some of nicotine’s acute subjective and physiological effects, while improving the sustained attention and cigarette craving in abstinent smokers, suggests that galantamine may act like a nicotine agonist similar to nicotine replacement therapy. This therapy, while reducing the acute subjective response to nicotine, also alleviates withdrawal symptoms and improves cognitive performance during abstinence.

The evidence from preclinical studies also suggests an agonist-like effect with galantamine. In fact, galantamine produced a partial generalization to nicotine’s discriminative stimulus effect in rats.7 Furthermore, galantamine reversed the deficit in contextual conditioning induced by nicotine withdrawal in mice.8 Galantamine acutely potentiates nicotinic currents induced by nAChR agonist such as ACh or nicotine in cell cultures.9

These findings along with those of other studies are consistent with the agonist effects of galantamine on nAChRs and provide potential mechanisms of action for the proposed therapeutic effect of galantamine on nicotine addiction.


Galantamine diminishes cigarette
craving and sustained attention
function suggesting that
it may have therapeutic value for
smoking cessation.


Among the limitations of the Yale study was that they used only one dose of galantamine, 8 mg/day, which is lower than the usual clinical doses ranging from 8 to 24 mg/day. A second limitation is that the treatment duration was brief, only 4 days. It is possible that longer treatment with galantamine may produce different effects. A third limitation is that the cognitive assessment did not include a battery of tasks that are needed to better examine the cognitive effects of galantamine in abstinent smokers. Finally, the study consisted mostly of men and included multiple measurements of different domains, increasing the probability of false positive type errors. Considering these limitations, the study findings should be regarded as preliminary.

Galantamine for Reduced Tobacco Craving and Cessation

In summary, galantamine diminishes cigarette craving and sustained attention function suggesting that it may have therapeutic value for smoking cessation. The findings are also supported by previous work conducted with other AChEIs. Nicotine reward, reinforcement, withdrawal, and cognitive difficulties have been proposed as potential treatment targets to develop novel treatments for nicotine addiction.

Galantamine reduced the self-reported rating of “craving for cigarettes” and prevented decrements in performance in a Go/No-Go task. In response to IV nicotine, galantamine treatment offset the self-report ratings of “like the drug effects,” “good drug effects,” “bad drug effects,” and “stimulated.” These findings support the potential utility of galantamine as a treatment for smoking cessation.

References

  1. Herman AI, Sofuoglu M. Comparison of available treatments for tobacco addiction. Curr Psychiatry Rep 2010 Oct;12(5):433-40.
  2. McEvoy JP. Galantamine’s effect on smoking in schizophrenics. Program and abstracts of the XII World Congress of Psychiatry, August 24-29, 2002, Yokohama, Japan. Abstract PO-74-10.
  3. Diehl A, Nakovics H, Croissant B, Smolka MN, Batra A, Mann K. Galantamine reduces smoking in alcohol-dependent patients: a randomized, placebo-controlled trial. Int J Clin Pharmacol Ther 2006 Dec;44(12):614-22.
  4. Hopkins TJ, Rupprecht LE, Hayes MR, Blendy JA, Schmidt HD. Galantamine, an acetylcholinesterase inhibitor and positive allosteric modulator of nicotinic acetylcholine receptors, attenuates nicotine taking and seeking in rats. Neuropsychopharmacology 2012 Jun 6. doi: 10.1038/npp.2012.83. [Epub ahead of print]
  5. Sofuoglu M, Herman AI, Li Y, Waters AJ. Galantamine attenuates some of the subjective effects of intravenous nicotine and improves performance on a Go No-Go task in abstinent cigarette smokers: a preliminary report. Psychopharmacology (Berl). 2012 Jun 15. [Epub ahead of print]
  6. Diehl A, Nakovics H, Croissant B, Smolka MN, Batra A, Mann K. Galantamine reduces smoking in alcohol-dependent patients: a randomized, placebo-controlled trial. Int J Clin Pharmacol Ther 2006;44:614–22.
  7. Giarola A, Auber A, Chiamulera C. Acetylcholinesterase inhibitors partially generalize to nicotine discriminative stimulus effect in rats. Behav Pharmacol 2010;22:1–6.
  8. Wilkinson DS, Gould TJ. The effects of galantamine on nicotine withdrawal-induced deficits in contextual fear conditioning in C57BL/6 mice. Behav Brain Res 2011;223:53–7.
  9. Schrattenholz A, Pereira EF, Roth U, Weber KH, Albuquerque EX,Maelicke A. Agonist responses of neuronal nicotinic acetylcholine receptors are potentiated by a novel class of allosterically acting ligands. Mol Pharmacol 1996;49:1–6.


Will Block is the publisher and editorial director of Life Enhancement magazine.

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