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Acetylcholine Enhancement: Galantamine and DMAE’s Cognitive Supportive Role

Galantamine and DMAE’s Cognitive Supportive Role

By Ward Dean, MD

Cognitive function is controlled by the central nervous system, which in turn is controlled by the cholinergic system, a system of cells that produce and/or are stimulated by acetylcholine, a neurotransmitter that plays an integral role in learning and memory. Receptors respond to acetylcholine to facilitate intracellular communication, memory processing and higher cognitive functions. Acetylcholine is rapidly broken down by an enzyme, acetylcholinesterase (AchE), and made available to be recycled.

Diminished cholinergic functioning, a biomarker of normal aging, is especially severe in cases involving dementia. In Alzheimer’s for example, amyloid plaque deposits in key components of the cholinergic system cause a drastic decline in acetylcholine levels. To make matters worse, already reduced acetylcholine levels continue to be degraded by AchE, further impairing memory and eroding cognitive ability.

Acetylcholinesterase inhibitors that suppress acetylcholinesterase to prevent it from degrading acetylcholine allow the neurotransmitter to persist in the synaptic cleft for a longer period of time, enhancing cognitive function.

Galantamine, a natural compound derived from the common snowdrop (Galanthus nivalis), is a natural acetylcholinesterase inhibitor. It also potentates cholinergic receptors.1

Galantamine is extremely well studied, and research has accumulated to expand upon the already extensive evidence in support of galantamine’s cognitive-enhancing abilities. This article will review those new studies and discuss another natural agent, Dimethylaminoethanol (DMAE) that can be used in conjunction with galantamine to enhance cognitive abilities.

Galantamine and Cognitive Enhancement

One of the most recent studies on galantamine demonstrated that it does act as an acetylcholinesterase inhibitor in Alzheimer’s patients. The researchers investigated galantamine’s effects in 18 patients with mild Alzheimer’s disease. The first three months of the study had a randomized double-blind placebo-controlled design, during which 12 patients received galantamine (16-24 mg per day) and six patients received a placebo. This was followed by nine months’ galantamine treatment in all patients. In patients on galantamine, acetylcholinesterase inhibition was 30-36 percent in the cerebrospinal fluid, which correlated well with the in vivo acetylcholinesterase inhibition in the brain. No significant acetylcholinesterase inhibition was observed in the placebo group. The acetylcholinesterase inhibition that occurred after galantamine positively correlated with the patients’ performance on cognitive tests.2

Brodaty et. al. recently conducted another human trial of galantamine in Alzheimer’s patients. In this prospective, open-label, observational study, 345 subjects with mild to moderately severe dementia of the Alzheimer’s type were recruited from 48 hospitals in Australia. Subjects received galantamine for six months in a clinical practice setting. The participants were assessed at baseline and three and six months after starting galantamine. The researchers used a number of tests to determine the subjects’ cognitive function, including the Mini-Mental State Examination (MMSE), the Clinician’s Interview-Based Impression of Change plus Caregiver Input (CIBIC-plus) and the Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog). Researchers also used an abridged Instrumental Activities of Daily Living (IADL) questionnaire that included questions on using the telephone, ability to travel more than 1 km outside the home, taking medications and managing money, and an 11-item behavior assessment scale that measured aggression, sleep disturbance, disinhibition, personality changes, irritability, depression, agitation, apathy, inertia, hallucinations and aberrant motor behavior.

Of the 345 subjects who were enrolled in the study, 229 completed the baseline and three- and six-month visits. At 6 months of galantamine usage, most subjects (70 percent) showed an increase in MMSE score. Of the 21 patients who were assessed using the Alzheimer’s Disease Assessment Scale-cognitive subscale, 18 (86 percent) demonstrated a decrease in the ADAS-cog score, reflecting an improvement in cognition. Most subjects (86 percent) were considered responders according to the Clinician’s Interview-Based Impression of Change plus Caregiver Input score, with 65 percent showing some improvement over six months of galantamine use. No deterioration in Instrumental Activities of Daily Living or behavior assessments occurred in the majority of subjects over six months.3

According to the researchers, “In a clinical practice setting, the majority of subjects receiving galantamine who completed the study maintained their ratings of cognition, function, behaviour or global assessment over the 6-month period.”

Due to the promising research that exists supporting galantamine’s ability to improve cognitive function, researchers have begun to delve more deeply into exactly how galantamine might exert its effects. In a recent animal study, the scientists noted that rodents given galantamine experienced an increase in extracellular levels of dopamine, which is the immediate precursor in norepinephrine synthesis. Norepinephrine is a neurotransmitter and a disturbance in its metabolism at important brain sites has been associated with cognitive disorders.

In the above study, researchers used a mouse model of Alzheimer’s disease to investigate galantamine’s effects. They injected mice with beta amyloid, a protein implicated in Alzheimer’s disease. Compared to saline injected mice, animals injected with the amyloid protein could not discriminate between new and familiar objects in the novel object recognition test and exhibited less freezing response in the fear-conditioning tasks, suggesting the amyloid protein induced cognitive impairment. When these animals were given galantamine, it improved the beta amyloid induced cognitive impairment in the novel object recognition and fear-conditioning tasks. Galantamine also significantly increased the extracellular dopamine release in the hippocampus of the animals. However, when the animals were given galantamine along with agents that block dopamine, the same improvements were not noted.

The study authors noted that this is the first in vivo evidence that galantamine augments dopaminergic neurotransmission within the hippocampus by enhancing the activity of acetylcholine receptors.4

Smoking Cessation

One of the most interesting new studies on galantamine investigated its effects in smoking cessation. Researchers studied whether galantamine reduces smoking by performing a 24-week randomized, placebo-controlled, multicenter clinical trial in 114 recently detoxified alcohol-dependent patients. They included all study subjects irrespective of an intention or motivation to abstain from nicotine. Specific treatment for cessation or reduction of smoking was not provided. The scientists determined smoking behavior through patients’ diaries and measured the nicotine metabolite cotinine to verify the number of smoked cigarettes. Fifty-six of the smokers were randomized to receive galantamine while 58 received a placebo for 12 weeks. Smoking behavior did not differ between both groups at baseline.

Analysis revealed significant differences between groups, with a 20 percent lower cumulative number of smoked cigarettes and a 15 percent 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 values decreased about 10 percent in the galantamine group.5

According to the researchers, “Our tentative data indicate that galantamine reduces smoking behavior even without any additional specific intervention. We suggest introducing the term ‘substitution therapy’ into the treatment of smoking. This result could open up a new treatment approach for groups of patients which usually have a low motivation for change.”

Autism

Because abnormalities in acetylcholine metabolism have been associated with autism, scientists recently investigated the use of galantamine in children with this disorder. Thirteen medication-free children with autism (mean age, 8.8 years) participated in a 12-week, open-label trial of galantamine. Patients were rated monthly by parents on the Aberrant Behavior Checklist (ABC) and the Conners’ Parent Rating Scale-Revised, and by a physician using the Children’s Psychiatric Rating Scale and the Clinical Global Impressions scale.

Autistic children using galantamine showed a significant reduction in parent-rated irritability and social withdrawal on the ABC as well as significant improvements in emotional lability and inattention on the Conners’ Parent Rating Scale–Revised. Similarly, clinician ratings showed reductions in the anger subscale of the Children’s Psychiatric Rating Scale. Eight of 13 participants were rated as responders on the basis of their improvement scores on the Clinical Global Impressions scale. Overall, galantamine was well-tolerated, with no significant adverse effects apart from headaches in one patient.6

“In this open trial,” the researchers wrote, “galantamine was well-tolerated and appeared to be beneficial for the treatment of interfering behaviors in children with autism, particularly aggression, behavioral dyscontrol, and inattention. Further controlled trials are warranted.”

DMAE and Cognitive Enhancement

Along with galantamine, DMAE is important to include in a list of cognitive-enhancing substances. Dimethylaminoethanol (DMAE) is a naturally-occurring, mild cerebral stimulant nutrient found in such “brain” foods as anchovies and sardines.

Like galantamine, DMAE influences acetylcholine metabolism (Fig. 1). It has long been known to stimulate the production of choline, which in turn allows the brain to optimize production of acetylcholine.7-9 However, Professor Imre Zs.-Nagy believes that enhanced acetylcholine is not the only explanation for DMAE’s effect, since he believes that a choline-rich diet alone should have the same acetylcholine-increasing effect, which he believes is not the case. Zs.-Nagy proposes that other mechanisms of DMAE include its being a free radical scavenger (with particular ability to protect cellular membranes); cross-linkage inhibitor; and spin trapper (a type of free radical scavenger).10 In addition, Dr. Richard Hochschild proposed that DMAE’s principal anti-aging mechanism is that of acting as a “cell membrane fluidizer.”11

Acetylcholine

DMAE has been used for years to improve behavioral disorders in children, and results in positive effects on intelligence and grades as well. DMAE produces a mild stimulant effect, which develops slowly over a period of several weeks. There is no drug-like letdown or depression if it is discontinued.12

In 1958, Dr. Leon Oettinger, Jr., found that DMAE:13

  • Accelerated mental processes
  • Improved concentration
  • Stopped early morning “fogginess”
  • Relieved lassitude and mild depression
  • Was useful in schizophrenia of long duration (with prolonged treatment)
  • Decreased irritability and reduced overactivity, leading to a much better overall social adaptation and improved scholastic functioning
  • Increased attention
  • Did not cause drowsiness
  • Improved IQ.

Furthermore, Dr. Oettinger found that DMAE had numerous advantages over the amphetamines (like Ritalin) in that there were no effects on heart rate or blood pressure and no induced “jitteriness.” Instead of causing anorexia (loss of appetite) like the amphetamines, he found that DMAE actually improved appetite in many patients and caused no interference with sleep. In fact, he found that DMAE actually reduced sleep requirements. Dr. Oettinger concluded that DMAE “was a most useful tool in the handling of the child with behavioral problems.”

In 1960, Dr. Stanley Geller reported on a double-blind study of 75 children, that DMAE in doses of 50 mg twice daily resulted in improved functioning capacity, puzzle-solving ability and organization of activity.14

In another double-blind study of fifty children who had been diagnosed as suffering from “hyperkinetic syndrome,” DMAE was administered in doses up to 500 mg/day (300 mg in the morning; another 200 mg at lunch). The authors concluded that DMAE, “when administered at doses of 300 to 500 mg per day for 12 weeks to moderately disturbed hyperkinetic children (six to 12 years of age) produces greater overall improvement in comparison to patients similarly treated with a placebo.”15

Although most of the human studies involving DMAE and cognitive enhancement seem to have been conducted in the 1950s and 1960s, a recent animal study confirmed the memory/intelligence-improving effects of DMAE. Animals fed DMAE were better able to negotiate a maze compared to untreated animals.16

Chronic Fatigue and Depression

DMAE has been demonstrated to be useful in chronic fatigue as well as in depression in children.17 It also normalizes brain function and mood.18

A recent study in Germany evaluated the effects of DMAE in subjects suffering from borderline emotional disturbance and depression, using a combination of EEG (electroencephalogram) and psychometric testing. The scientists found that DMAE use resulted in decreased theta and alpha1 waves, characteristic of increased vigilance and attention. In addition, the subjects reported increased activity and better mood. The authors concluded that DMAE induces a psychophysiological state of enhanced well being as corroborated by mood analysis and brain electrical activity.19

Parkinson’s

DMAE improves movement disorders and prevents adverse effects of L-Dopa in Parkinsonism. In 1974, Dr. Edith Miller added DMAE in doses ranging from 300 to 900 mg per day to the regimen of Parkinson’s patients, who had begun to exhibit adverse effects from high dosages of L-Dopa (L-3, 4-dihydroxyphenylalanine, administered to treat Parkinson’s Disease). DMAE administration resulted in a complete resolution of the L-Dopa-induced abnormal movements (diskenesias) in a majority of the patients.20

Dr. Miller concluded that “DMAE seems to be the first effective measure to combat L-Dopa-induced dyskinesias safely and effectively without interfering with the beneficial effects of L-Dopa therapy.” Studies in an animal model subsequently produced similar results.21 DMAE also has been shown in humans to reduce other involuntary movement disorders, including benign essential tremor and even blepharospasm (eyelid twitching). Use of DMAE resulted in improvement in all symptoms, with the exception of those suffering from Huntington’s chorea.22

Age Spots

One of the most dramatic and well-documented effects of DMAE is its ability to inhibit the formation of aging pigment (lipofuscin)—the brownish pigment that causes “liver spots” (lentigo) on the backs of the hands of many people over 50 years of age.

DMAE not only can prevent the formation of lipofuscin, but it also actually flushes it from the body.23 Many people gauge the rate of lipofuscin removal from their hearts and brains by watching their “liver spots” disappear with long-term supplementation of DMAE. It usually takes about six months for significant changes to take place—with many spots resolving completely.

Conclusion

A recent study reports that approximately 24 million people suffer from dementia worldwide. If the mortality rate does not change and no curative or preventive treatment is developed, this number is expected to double every 20 years.24

With this threat hanging over our heads, DMAE and galantamine deserve high rankings on the list of cognitive-enhancing supplements. Each of these natural agents has a long track record of safety and efficacy, and ongoing research continues to add to the already impressive list of potential benefits.

References

1. Lenzken SC, Lanni C, Govoni S, Lucchelli A, Schettini G, Racchi M. Nicotinic component of galantamine in the regulation of amyloid precursor protein processing. Chem Biol Interact. 2007 Jan 30;165(2):138-45. Epub 2006 Dec 1.

2. Darreh-Shori T, Kadir A, Almkvist O, Grut M, Wall A, Blomquist G, Eriksson B, Langstrom B, Nordberg A. Inhibition of acetylcholinesterase in CSF versus brain assessed by (11)C-PMP PET in AD patients treated with galantamine. Neurobiol Aging. 2006 Dec 28; [Epub ahead of print].

3. Brodaty H, Woodward M, Boundy K, Barnes N, Allen G. A naturalistic study of galantamine for Alzheimer’s disease. CNS Drugs. 2006;20(11):935-43.

4. Wang D, Noda Y, Zhou Y, Mouri A, Mizoguchi H, Nitta A, Chen W, Nabeshima T. The Allosteric Potentiation of Nicotinic Acetylcholine Receptors by Galantamine Ameliorates the Cognitive Dysfunction in Beta Amyloid(25-35) I.c.v.-Injected Mice: Involvement of Dopaminergic Systems. Neuropsychopharmacology. 2006 Nov 29; [Epub ahead of print].

5. 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.

6. Nicolson R, Craven-Thuss B, Smith J. A prospective, open-label trial of galantamine in autistic disorder. J Child Adolesc Psychopharmacol. 2006 Oct;16(5):621-9.

7. London ED, Coyle JT. Pharmacological augmentation of acetylcholine levels in kainate lesioned rat striatum. Biochem Pharmacol. 1978;27: 2962-2965.

8. Haubrich DR, Wang PF, Clody DE, Wedecking PW. Increase in rat brain acetylcholine induced by choline or deanol. Life Sci. 1975, 17: 975-980.

9. Jope RS, Jenden DJ. Dimethylaminoethanol (deanol) metabolism in rat brain and its effect on acetylcholine synthesis. J Pharmacol Exp Ther. 1979; 211:472-479.

10. Zs.-Nagy I. Pharmacological interventions against aging through the cell plasma membrane — a review of the experimental results obtained in animals and humans, Annals of the New York Academy of Sciences. 2002; 959:308-320.

11. Hochschild R. Effect of dimethylaminoethanol on the life span of senile male A/J mice. Exp Gerontol. 1973;8(4): 185-191.

12. Pfeiffer GC. Parasympathetic neurohormones. possible precursors and effect on behavior. Int Review of Neurobiology. 1959;195-244.

13. Oettinger L. The use of Deanol in the treatment of disorders of behavior in children. J Pediat.1958;53:761-675.

14. Geller SJ. Comparison of a tranquilizer and a psychic energizer. JAMA 1960;174:89-92.

15. Coleman N, Dexheimer P, Dimascio A, Redman W, Finnerty, R. Deanol in the treatment of hyperkinetic children. Psychosomatics. 1976;17:68-72.

16. Levin ED, Rose JE, Abood L. Effects of nicotinic dimethylaminoethyl esters on working memory performance of rats in the radial-arm maze. Pharmacol Biochem Behav. 1995 Jun-Jul;51(2-3):369-73.

17. Kugel RB, Alexander T. The effect of a central nervous system stimulant (Deanol) on behavior. Pediatrics. 1963;31: 651-655.

18. Sergio W. Use of DMAE in the induction of lucid dreams. Med Hypotheses. 1988; 26(4): 255-257.

19. Dimpfel W, Wedekind W, Keplinger I. Efficacy of dimethylaminoethanol (DMAE) containing vitamin-mineral drug combination on EEG patterns in the presence of different emotional states. Eur J Med Res. 2003 May 30;8(5):183-91.

20. Miller E. Deanol (DMAE) in the treatment of levodopa-induced dyskinesias. Neurology. February 1974;116-119.

21. Davis KL, Hollister LE, Vento AL, Beilstein BA, Rosekind GR. Dimethylaminoethanol (deanol): effect on apomorphine-induced stereotype and an animal model of tardive dyskinesia. Psychopharmacology (Berl). 1979 May 25;63(2):143-6.

22. Daniel E. Mood alterations during deanol therapy. Psychopharmacology. 1979;62 (2):187-191.

23. Zs.-Nagy I., Floyd RA. Electron spin resonance spectroscopic demonstration of the hydroxyl free radical scavenger properties of dimethylaminoethanol in spin trapping experiments confirming the molecular basis for the biological effects of centrophenoxine. Arch Gerontol Geriatr. 1984 Dec;3(4):297-310.

24. Popa RV, Pereira EF, Lopes C, Maelicke A, Albuquerque EX. The N-butylcarbamate derivative of galantamine acts as an allosteric potentiating ligand on alpha7 nicotinic receptors in hippocampal neurons: clinical implications for treatment of Alzheimer’s disease. J Mol Neurosci. 2006;30(1-2):227-32.

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