Galantamine’s Versatility Grows AgainGalantamine May Help in Schizophrenia
Cognitive deficits associated with schizophrenia suggest an effective remedy—for them
By Will BlockIf you talk to God, you are praying. If
God talks to you, you have schizophrenia.
— Thomas Szasz
ou’re out on the road, and your car starts sputtering and lurching. You know you’re not out of gas, so that can’t be the problem. You get out, open the hood of your car, and have a look. Intimidating, isn’t it? Unless you actually know something about auto mechanics, you stare uncomprehendingly at the engine compartment. Good grief, what is all that stuff, and what part of it has gone bad? You don’t have a clue what to look for, let alone what to do even if you were somehow to stumble upon the problem. Time to call AAA.
Now image you’re a doctor faced with a patient who has started sputtering and lurching, so to speak. The patient hasn’t run out of gas either, but things under the “hood” are clearly not working right. What do you do? Opening the hood is usually not an option (patients hate it when you do that), and even if you did, the next step wouldn’t be as simple as replacing a few broken parts—even if you knew which ones they were. So you have to try, with your hands tied, to ascertain what’s wrong in there, and fix it if you can. And what’s in there is incomparably more complex—not to mention more valuable to you—than any auto engine.
How Doctors Earn Their Fees
Challenging, no? No wonder doctors earn more than auto mechanics (although it doesn’t seem that way when you get your car fixed, does it?). Of course, doctors do have some fancy brain-imaging tricks up their sleeve, such as CT (computed tomography), MRI (magnetic resonance imaging), and PET (positron emission tomography). Each of these high-tech methods can give, in its own way, a partial picture of brain structure or neural activity, allowing the doctor to “see” a little of what’s cooking (or not cooking) inside your head.
Based on that information, together with a number of other factors—the patient’s physical condition, medical history, lab results, performance on cognitive tests, and emotional state, as well as descriptions of symptoms by the patient and by the patient’s family members or other caregivers—the doctor must decide on an appropriate treatment. If an aging patient shows evidence of substantial cognitive deficits, such as memory loss, impaired attention, or impaired learning ability, the doctor will undoubtedly suspect central cholinergic dysfunction, because disruptions of the cholinergic component of the central nervous system underlie most of the mental problems of old age. (See the sidebar “The Cholinergic System.”)
The Cholinergic System
In certain portions of the human brain—including the hippocampus, which is ground zero for much of the neural activity involved in memory and learning—molecules of acetylcholine are the principal neurotransmitters. These portions of the brain constitute the central cholinergic system.* Cholinergic means “activated by or capable of liberating acetylcholine”; it also means “having physiological effects similar to those of acetylcholine.”
When a nervous impulse flows (as a tiny electric current) through a cholinergic neuron and reaches the nerve ending, acetylcholine (ACh) molecules are liberated from the nerve ending and transmit the impulse by zipping across the synapse to the adjacent nerve ending. There the ACh molecules find and momentarily attach themselves to ACh receptor sites—protein complexes that are specifically designed to recognize ACh molecules and respond to them in such a way that the nervous impulse continues to flow. A vital feature of these (and other) molecular receptors in the brain is that they can also respond, in various ways, to certain other molecules that are, in effect, ACh mimics.
There are two main kinds of acetylcholine receptors, whose functions are in part the same and in part complementary. One kind is nicotinic ACh receptors, so named because they’re particularly sensitive to nicotine, a poisonous alkaloid that nonetheless has a positive effect on cognition through its cholinergic activity. The other kind is muscarinic ACh receptors, so named because of their sensitivity to muscarine, which also happens to be poisonous (it’s found in the mushroom Amanita muscaria and in decaying animal tissue).
How strange that the two major categories of acetylcholine receptors are named for deadly poisons that happen to be beneficial to us—but only in trace amounts, so don’t start smoking or eating poisonous mushrooms!
Is It Dementia or Not?
The symptoms described above are those of dementia, and they can be effectively counteracted, to a significant degree and for a significant period of time, by galantamine, a natural supplement that is procholinergic, i.e., it enhances cholinergic function. Dementia can be of numerous kinds. The most prevalent by far is Alzheimer’s disease, followed by Lewy body dementia, vascular dementia, Parkinson’s disease dementia, and others.* They all have common features, but with variations on the theme that can help doctors in making a diagnosis—especially if they use brain-imaging techniques to augment the more traditional means of examination.
But what if there are other kinds of symptoms as well, such as hallucinations? These are not common in Alzheimer’s disease, although they are characteristic of Lewy body dementia, and they also occur in Parkinson’s disease dementia. And what about delusions and paranoia, which are also uncharacteristic of Alzheimer’s but which do occur with Lewy body and Parkinson’s? Now the doctor’s diagnostic challenge gets trickier, because, although these could be symptoms of some dementias, they could also be symptoms of a different kind of disease: schizophrenia.
Schizophrenia Can Make You Crazy
Schizophrenia, by the way, does not mean a split personality (even though the term comes from the Greek words for “split mind”)—scientists no longer give credence to that simplistic notion. It’s a type of psychotic disorder usually characterized by a withdrawal from reality, illogical thought patterns, hallucinations, delusions, and paranoia, accompanied in varying degrees by other emotional, behavioral, or intellectual disturbances. In short, it’s quite different from dementia.* That should make a diagnosis easier—but there’s still this to consider: just as demented patients can have some of the psychotic symptoms that are characteristic of schizophrenia, so schizophrenic patients can have some of the cognitive-deficit symptoms that are characteristic of dementia.
Why Galantamine Should Help
That crossover effect has led scientists to suspect that schizophrenia, like dementia, is at least in part a disease of cholinergic dysfunction. And if that is true, then procholinergic agents such as galantamine might be helpful. A scientist at the Mount Sinai School of Medicine in New York has published a review of the literature on this subject, marshaling evidence to support this view.
The animal studies cited involved pharmacological manipulation of the central cholinergic system. Anticholinergic agents, such as atropine and scopolamine, were administered, producing memory deficits. These deficits could then be effectively reversed by administering procholinergic agents, such as physostigmine and donepezil (an anti-Alzheimer’s drug). (See the sidebar “The Schizophrenic Nature of Some Drugs.”)
The Schizophrenic Nature of Some Drugs
Remember the adage, “One man’s medicine is another man’s poison”? (OK, it was “meat,” but let’s not quibble.) As this article is being written, Bush and Kerry are flailing away at each other over various issues, including the soaring cost of pharmaceuticals and the difficulty for many senior citizens to afford them. What one candidate offers as a cure for the problem, the other denounces as foolish and destructive. It’s the old medicine/poison story. (During a previous presidential campaign, David Letterman said, “With two such fine candidates, it’s just a darn shame that both of them can’t lose.”)
Ironically, the word “pharmaceutical” is derived from a Greek word, pharmakon, meaning both “medicine” and “poison”! As paradoxical as this may seem at first, it starts to make sense when we remember that virtually anything that’s good for our health can also do us harm in too large a dose. Vitamin A and iron are two well-known examples, but there is a risk inherent in overdoing just about anything—even water.
On the other hand, substances that are generally dangerous can be harmless or even beneficial in very low doses. Strychnine, belladonna, and morphine are three examples of highly toxic substances that have medicinal value when used in suitably small amounts under the direction of a physician. Another well-known medicine that can be lethal—in a dramatically different way—is nitroglycerine. And now there’s botox—a virulent toxin for banishing those frown lines.
There’s also nicotine, one of the most poisonous substances known to man—one drop of the liquid will kill you—yet in very low doses it’s a potent memory- and cognition-enhancing drug, owing to its stimulation of the brain receptors that bear its name: nicotinic acetylcholine receptors. (Please do not take this as a reason to smoke!)
Although you may not have realized it, you do get nicotine in tiny amounts from such items as eggplants, potatoes, and tomatoes. Remarkably, these nutritious foods belong to the same notorious Solanaceae family that includes the toxic herbs henbane, mandrake, jimsonweed, and deadly nightshade, among others. These herbs have been used as poisons and hallucinogens by resourceful people for millennia. Two of the active compounds involved are the alkaloids atropine and scopolamine, which cloud the mind, inducing a state of oblivion. An antidote is galantamine, which acts to preserve and protect memory function. (See the sidebar
“Of Goddesses and Tomatoes” in the article “Galantamine Opens the Channels of Your Memory” in the January 2002 issue.)
- Levin ED. Nicotinic Receptors in the Nervous System. CRC Press, Boca Raton, FL, 2002.
Similar results have been observed in experiments with human volunteers, and the evidence suggests that the memory impairments of schizophrenic patients may be particularly responsive to procholinergic agents (of which galantamine is the most effective, overall, among the agents used to treat Alzheimer’s disease).
The Blame Game
Some studies have implicated the brain’s nicotinic acetylcholine receptors (see the first sidebar cited above) as being involved in the cholinergic dysfunction associated with schizophrenia, which suggests that procholinergic agents with a positive effect on these receptors should be effective in treating the disease (the cognitive aspects of it, at any rate). Other studies have implicated the muscarinic acetylcholine receptors, suggesting that procholinergic agents with a positive effect on these receptors should also be effective. Evidently there’s enough blame—and potential treatment options—to go around.
Two compounds have been the procholinergic agents of choice in cognitive enhancement trials with schizophrenic patients: the prescription drug donepezil and the natural supplement galantamine (which is also sold as a prescription drug). Both are acetylcholinesterase inhibitors, i.e., they inhibit the action of the enzyme that destroys acetylcholine (ACh) molecules. Only galantamine, however, is a modulator of nicotinic ACh receptors, i.e., it interacts with these receptors in such a way as to help prevent them from becoming desensitized to ACh molecules, and to help prevent their deterioration and loss (which are characteristic in Alzheimer’s). The net effect is to maintain viable cholinergic function.
Donepezil Was Not Very Effective
As described in the review paper cited above, the three published studies on donepezil in schizophrenia (two open-label and one double-blind, placebo-controlled) gave poor results at best, but the author explains why, for various reasons (including poor study design in two cases), this might have been expected. One problem may have been the fact that the vast majority of schizophrenics are heavy smokers (they smoke to obtain the stimulatory effects of nicotine on their cognitive function, despite the damage it does to almost every other aspect of their health—they must be crazy). It’s possible that smoking desensitizes the nicotinic ACh receptors to increased ACh levels caused by a drug such as donepezil.
Galantamine Helped Despite the Smoking
One galantamine study (double-blind, placebo-controlled) was discussed in the review. As in the donepezil studies, the patients were taking an antipsychotic drug (in this case, risperidone, which has minimal anticholinergic activity) to control other aspects of their disease. For this study, 24 schizophrenic patients (all of them smokers) were randomized into four groups: one placebo group and three treatment groups receiving 16, 24, or 32 mg/day of galantamine.
The results showed that the higher doses of galantamine were associated with significantly greater improvements in what was described as “continuous performance task (CPT) errors of commission and verbal fluency test performance.” An intriguing aspect of this study was that galantamine enhanced the patients’ cognitive performance despite their being smokers—a testimonial, perhaps, to galantamine’s potency as a modulator of nicotinic ACh receptors as well as an acetylcholinesterase inhibitor.
Where There’s Galantamine, There’s Hope
Schizophrenia is a major public health problem throughout the world, affecting about 1% of the population, although pockets of higher or lower incidence have been identified. In the United States, people with schizophrenia occupy about one-fourth of all the hospital beds and account for about one-fifth of all Social Security disability days. Schizophrenia is more prevalent than Alzheimer’s disease, diabetes, or multiple sclerosis. Although there is no cure, it’s gratifying to know that it may be possible to alleviate at least some of the symptoms of this terrible disease with galantamine.*
- Friedman JI. Cholinergic targets for cognitive enhancement in schizophrenia: focus on cholinesterase inhibitors and muscarinic agonists. Psychopharmacol 2004;174:45-53.
- Allen T, McEvoy JP, Keefe R, Levin E, Wilson W. Galantamine as an adjunctive therapy in the treatment of schizophrenia. Presented at 11th Congress of the International Psychogeriatric Association (IPA), Chicago, IL, Aug 17-22, 2003.
- Berkow R, et al., eds. The Merck Manual of Medical Information—Home Edition. Pocket Books, New York, 1997.
Galantamine provides a heralded dual-mode action for boosting cholinergic function: it inhibits the enzyme acetylcholinesterase, thereby boosting brain levels of acetylcholine, and it modulates the brain's nicotinic receptors so as to maintain their function. The recommended daily serving ranges from a low of 4 to 8 mg of galantamine to begin with to a maximum of 24 mg, depending on the individual's response.
For an added measure of benefit, it is a good idea to take choline, the precursor molecule to acetylcholine, as well as pantothenic acid (vitamin B5), an important cofactor for choline. Thus it is possible to cover all bases in providing the means to enhance the levels and effectiveness of your acetylcholine.
Will Block is the publisher and editorial director of Life Enhancement magazine.