Galantamine Opens the Channels of Your Memory
The secret of galantamine's success lies in your brain's nicotinic receptors
by Will Block

The secret of galantamine's success lies in your brain's nicotinic receptors.
Take galantamine. Really - take it. If you do, a remarkable molecular drama will unfold in your brain, enhancing the mechanism by which your thoughts travel through complex neural circuits to become deposited somewhere as memories. To see how this occurs, imagine that your eyes are incredibly powerful microscopes, able to peer into the heart of matter and observe individual molecules.  If you used this awesome power to look inward at your own brain, what would you expect to see?  Probably lots of icky stuff that you'd rather not think about (even though you think with it).

But wait: focus on a synapse - the tiny space between two adjacent neurons (nerve cells), where swarms of neurotransmitters zip across the gap from one neuron to the next, carrying a thought of yours on molecular wings. If you look closely at the cell wall of one of the nerve endings, you will see something startling and strangely pretty: countless tiny molecular rosettes, called receptors, dotting the surface. Each rosette has a dimpled center that can, when signaled, open up to create a narrow channel through the cell wall into the dark interior of the nerve.

Each "petal" of the rosette - there are five petals - is a protein molecule. As molecules go, proteins are very large and complex, with many oddly shaped crevices into which much smaller molecules can fit, if they have exactly the right molecular structure for a particular crevice. Now imagine that you can see swarms of such smaller molecules zooming in on the protein petals, like hyperactive aphids on a flower. Some of them fit into specific crevices, called binding sites, on one petal or another for a split second; they then drift away, to be replaced quickly by another molecule of the same kind.

Ah, but during that split second, something very important happens: the rosette pulses, and the channel down the middle opens for an instant. During that instant, a few metal ions that were milling about in the fluid-filled synapse "shoot the chute" and vanish into the neuron's interior. All this happens thousands of times per second at each rosette, so your eyes better be quick as well as powerful.

The metal ions, believe it or not, are carrying that thought of yours (a fragment of it, anyway), perhaps to be stored somewhere far down the line as a memory - the name of a new friend, perhaps, or the square root of eleven. The neurotransmitters handed the thought off to the ions, like runners in a relay race. To be more accurate, the neurotransmitters and the metal ions (as well as other molecules and ions inside the nerves themselves) don't carry your thought - they are your thought. Think about that.

In any case, what enables this "relay-race transfer" to take place is the receptor. In this case, we're talking about a certain kind called a nicotinic receptor, because it's so sensitive to nicotine. Yes, that nicotine, which in very low doses is a potent memory- and cognition-enhancing drug.1 There are many other kinds of receptors throughout the nervous system, but the nicotinic ones are the stars of this drama, along with the galantamine molecule.

Most of the "aphids" in our biochemical drama are molecules of the neurotransmitter acetylcholine. Others, however, are molecules of galantamine - assuming you're wise enough to have been taking this natural supplement for its extraordinary capacity to enhance memory and cognition.

What galantamine does - and here's the rub, #1 - is something very special: when it binds to the protein "petal" (called a subunit, actually) at its special binding site, it modulates the protein's structure through intermolecular forces, changing it subtly in such a way as to make the receptor as a whole more responsive than normal to the presence of the acetylcholine molecules that bind to the protein subunits at their sites.  This causes the rosette to open more readily when triggered to do so by an acetylcholine "aphid" landing on it.

Thus galantamine facilitates more efficient transmission of neural signals down the channels of your memory.  Furthermore, galantamine exerts a protective effect on nicotinic receptors that tends to preserve their sensitivity to acetylcholine and to preserve the receptors themselves.  This is important because both the sensitivity of the receptors and the receptors themselves tend to erode away as our brains age - especially if they fall victim to the ravages of Alzheimer's disease.

That protective action is the real payoff of galantamine, a remarkable plant-based alkaloid that has a history of use for thousands of years and that has now become known as the most effective anti-Alzheimer's agent there is.  Neither of the two leading Alzheimer's drugs - donepezil and rivastigmine - fulfills this unique biochemical role as modulator of nicotinic receptors.*  Instead, they act in a very different way, as acetylcholinesterase inhibitors. That means that they inhibit the action of the enzyme acetylcholinesterase, which holds the levels of acetylcholine down - sometimes too far down, with negative effects on memory and cognition. So by inhibiting that enzyme, donepezil and rivastigmine free up more acetylcholine for use by your brain - and that's a good thing. 

*You may have heard about yet another Alzheimer's drug called tacrine, but forget about it. Tacrine is history - it's rarely prescribed any more because of its dangerous side effects. Now being prescribed, in addition to donepezil and rivastigmine, is a new drug whose trade name is ReminylŪ. The active ingredient in Reminyl is . . . galantamine!  The price for galantamine in that form is what one would expect for a prescription drug: steep. 

Let's summarize the situation: galantamine acts in one way (enhancing acetylcholine's effectiveness by modulating nicotinic receptors), whereas donepezil and rivastigmine act in another way (boosting acetylcholine levels by inhibiting acetylcholinesterase), right? Wrong, because - and here comes rub #2 - galantamine is also an excellent acetylcholinesterase inhibitor, so it acts in both ways to boost your mental function. This makes galantamine a double-duty agent unrivalled by any other molecule. (That's it - no more rubs. It's all downhill from here.)

Collectively, all the neurons in which these processes occur constitute the body's cholinergic nervous system. Cholinergic means "activated by or capable of liberating acetylcholine"; it also means "having physiological effects similar to those of acetylcholine." Because galantamine fills those bills, it is called, in the lingo of neurology, a cholinergic agonist - a spooky-sounding word that does not mean "causing agony." It means something that stimulates or enhances the activity of a natural agent, and its opposite is antagonist.

Disruption of the cholinergic system is believed to be largely responsible for the mental problems of old age, including Alzheimer's disease, which is primarily a condition of memory loss. A characteristic feature of this terrible disease is a complicated pattern of degenerative changes in the brain, including the atrophy or dysfunction of cholinergic cell groups that underlie the normal neural mechanisms associated with higher cognitive functions. There is also a progressive loss of nicotinic receptors in particular - a loss that is counteracted, as we already know, by the protective action of galantamine on these receptors.

Among the other forms of age-related cognitive impairment are confusion, delirium, hallucinations, and dementia. An important piece of evidence for the belief that cholinergic dysfunction is at the root of these disorders is the fact that they can be mimicked by taking various cholinergic antagonists, i.e., drugs that interfere with cholinergic activity.2 Throughout history, in fact, it has been a common practice in many cultures to take such drugs for ritualistic or sacred purposes, including initiation rites and religious ecstasies. (See the sidebar "Of Goddesses and Tomatoes.")

Of Goddesses and Tomatoes
The alkaloids atropine and scopolamine, which are cholinergic antagonists, are well-known examples of drugs that cloud the mind, inducing blissful forgetfulness. Some scholars believe that in the Greek epic the Odyssey, it was atropine - from jimsonweed, a plant native to the Mediterranean region - that the goddess Circe (who was quite a tomato) used to bewitch the crew of the hero Odysseus, inducing amnesia and a delusional state in which the men believed they had been turned into swine. 

The antidote that Odysseus used when he went to rescue his men from Circe's seductive spell is believed to have been galantamine, which comes from the snowdrop (Galanthus nivalis), a flower also native to that region.* The snowdrops were given to Odysseus by Hermes, the messenger of the gods. This may be the oldest known account of the use of an acetylcholinesterase inhibitor for reversing the effects of an anticholinergic drug.

*Galantamine is also extracted from certain other flowers, such as the daffodil (Narcissus pseudonarcissus L.), and the spider lily (Lycoris radiata).Most galantamine today comes from daffodils or is synthesized in the laboratory.

Among the favored sources of anticholinergic drugs, by the way, have been members of the botanical family called Solanacea, which is well known for its many poisonous plants (including jimsonweed). Oddly, the Solanacea family also includes our good friend the tomato (the kind you eat). When the Spanish conquistadors obtained tomatoes from the Aztecs and brought them back to Europe as a food, botanists there were horrified and declared that they must surely be poisonous.

It took a while for tomatoes to live down this bum rap and catch on, but it was worth the wait, because they eventually led to one of Western civilization's crown jewels: pizza. 

In performing its dual roles, galantamine acts as a powerful cognitive enhancer, helping to prevent age-related memory loss.  A meta-analysis - a thorough, critical review of the scientific literature - has recently been published, with results that confirm the role of galantamine as an effective treatment for Alzheimer's disease.

The authors combed medical journals and monographs, databases of clinical trials, and directories of Ph.D. theses for all available information on galantamine's role as a treatment for Alzheimer's. To ensure that only high-quality research was included in the meta-analysis, they screened the studies for the following factors: (1) they had to be randomized, double-blind, placebo-controlled, and unconfounded (i.e., galantamine had to be tested alone, not in combination with any other agent); (2) they had to have covered a treatment period of more than 4 weeks for patients with Alzheimer's disease; and (3) they had to meet additional criteria regarding the study protocol and the reporting of data. Of the 33 studies examined, only seven made the grade.

From the combined results of these seven studies - all of which involved patients with mildly to moderately severe Alzheimer's - the authors concluded: ". . . this review shows overall positive effects for galantamine for trials of 3 months, 5 months, and 6 months duration. . . . there is evidence demonstrating efficacy for galantamine on global ratings, cognitive tests, assessments of ADLs [activities of daily living], and behavior. This magnitude appears to be similar to other acetylcholinesterase inhibitors, including donepezil, rivastigmine, and tacrine."

In other words, in terms of cognitive function (memory and learning), galantamine works as well as the synthetic drugs. The dosages most commonly used in these studies were either 24 or 32 mg per day, but the authors concluded that 16 mg per day may be preferable, at least initially, because its efficacy is equal to that of the higher doses, and it is less likely to cause gastrointestinal upset.

Much of the evidence for the folkloric use of galantamine in Eastern Europe, where it is best known, pertains not to the improvement of cognitive function, but to the alleviation of neuromuscular ailments such as neuritis and neuralgia. Galantamine is also known to be a muscle stimulant (it counteracts the effects of the muscle relaxant curare, for example), and it is being recognized as beneficial for combating jet lag, fatigue syndromes, and even, perhaps, impotence.

From the foregoing list of effects, one might conclude that the cholinergic nervous system is not confined to the brain or even the central nervous system as a whole - and that's true. Indeed, most cholinergic neurons are somatic - out in the body, where acetylcholine acts as the primary neurotransmitter of the peripheral nervous system, for both skeletal muscles and smooth muscles (which are found in the walls of most internal organs). Here the acetylcholine molecules provide direct stimulation of the muscle cells at the neuromuscular junction - the somatic equivalent of a neural synapse within the brain. They also serve our exocrine glands, such as salivary and sweat glands, which secrete directly to the outside via ducts.

Wherever acetylcholine is - or ought to be in greater amounts than it actually is - galantamine can help increase its concentration and enhance its action. Galantamine's cholinergic activity throughout the body is also notable for its lack of toxicity and side effects. Part of its advantage over synthetic drugs in this regard may lie in the fact that it's about 50 times more effective in inhibiting acetylcholinesterase than in inhibiting butyrylcholinesterase, an enzyme that is apparently not involved in any cognitive function. By contrast, most other acetylcholinesterase inhibitors are also effective butyrylcholinesterase inhibitors, and it is believed that this may contribute to their peripheral toxicity.4

Galantamine is a highly effective inhibitor of acetylcholinesterase and modulator of nicotinic receptors and helps to preserve the function of the cholinergic system - all of which is beneficial for memory. Remember that.

  Galantamine  food for mind and body
Galantamine  rescues brain cells  
Galantamine  and memory enhancement
  Galantamine  fights Alzheimer's
  Galantamine  the old become young 


1. Levin ED. Nicotinic Receptors in the Nervous System. CRC Press, Boca Raton, FL, 2002. 

2. Perry EK. Cholinergic phytochemicals: from magic to medicine. Aging & Mental Health 1997;1(1):23-32. 

3. Olin J, Schneider L. Galantamine for Alzheimer's disease (Cochrane review). In The Cochrane Library, Issue 4, 2001. Oxford: Update Software. 

4. Barnes CA, Meltzer J, Houston F, Orr G, McGann K, Wenk GL. Chronic treatment of old rats with donepezil or galantamine: effects on memory, hippocampal plasticity, and nicotinic receptors. Neurosci 2000;99(1):17-23.

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