TRANSIENT GLOBAL AMNESIA ASSOCIATED WITH THE STATIN DRUGS
Presented at the Weston-Price Foundation Meeting,
3-5 May 2003, Wash. DC


By Duane Graveline MD MPH


Doc Graveline


Excerpted from the book:
Lipitor, Thief of Memory
, by Graveline and Richardson.
( Currently in the publication process.)

Try to imagine, if you can, the complete inability to formulate new memory. It is frightening even to consider a state of mind where you are unable to recall an event that just happened, even though it may have been extraordinarily important or meaningful to you. Picture a beautiful smile, a magnificent scene, or birth of a baby--even a tragic and terrible accident--disappearing like a tenuous wisp of smoke only moments after being experienced.
Almost everyone becomes aware at some point of the vagaries of memory, the reality that recall is not as precise as we would wish. Few can say with precision what they ate for breakfast two days ago or their exact words at a recent meeting but, early on, all of us learned to live with these minor and inconsequential shortcomings of recall for that is our nature. We expect precision from our computers but accept a certain flexibility of memory in our personal selves. When I say inability to formulate new memory, I am talking of the complete failure of the imprinting mechanisms. There can be no recall because there has been no memory processing. A person afflicted with this unfortunate problem is like a record with no grooves, a blank tape, a pristine computer disc with no information saved on it. For this innocent, this newborn babe, every passing moment is a new beginning. The victim has become like Voltaire’s Candide--unrehearsed and innocent, welcoming each new day with wonder and anticipation, oblivious to the fact that this scene has greeted his eyes many times previously. The past has lost its meaning for this poor soul. There is no past, only the present and future.
For most of us, amnesia of this type is something we have heard about when someone experiences head trauma, severe electric shock, stroke, certain cases of extensive brain surgery, or secondary to severe chronic alcoholism. These are all common causes of brain damage.
The literature is replete with case reports of this type, all of which make fascinating reading but they have only a superficial resemblance to the condition that is the genesis of this book: transient global amnesia (TGA.) This formerly rare condition, this morbidly fascinating end stage of memory dysfunction, is now known to be associated with the use of statin drugs. We have come to expect certain statin drug side effects such as occasional liver damage and muscle pain and even the dreaded rhabdomyolysis but the ever increasing cognitive side effects from these medications strike at who we are, our very essence. Without memory, what are we?
Transient global amnesia strikes without warning, abruptly depriving one of the ability to formulate new memories. With no record of the past, every new face, thought, conversation or scene is a unique moment, a novel experience transiently entering a mind suddenly emptied of the past. Think of the utter horror of this instant depersonalization, the anxiety, the frustration, the constant query, “What has happened to me?” Think of the concern of family and friends when their loved one is abruptly transformed into a querulous being who can walk and talk but who has suddenly been transformed into a bewildered creature without memory, pathetically attempting to cope with its strange new world.
This devastating world is known as transient global amnesia.
Years ago, when I was a medical student, transient global amnesia was very rare, almost a medical curiosity, and deserving of only a very limited description in most neurology textbooks. Fifty years would go by before I again encountered this obscure affliction, despite the fact that for at least twenty-five years of this time I operated a busy family practice seeing dozens of patients daily. Now, in the past several years, this condition has reached seemingly epidemic proportions in emergency rooms throughout North America and Europe. Emergency room doctors have hauled out their sometimes dusty medical books and looked with wonder from book to patient as they realize they are seeing what, for many, is their first case of transient global amnesia. These confused patients, asking over and over again, “What has happened to me?” or some similar question, are completely unable to remember the doctor’s explanation offered only moments before. For every case of this type of temporary amnesia, thousands of case reports of severe and incapacitating forgetfulness, disorientation and confusion have also been reported to statin drug researchers. Most of these cases do not make it to the emergency rooms and are no doubt extensively under reported.
All of these cases are associated with the use of the stronger statin drugs such as Lipitor, Mevacor and Zocor. Sometimes only weeks go by after the start of the medication before symptoms begin. In other cases several years might pass before the onset of symptoms. Frequently they have been associated with muscle pain and tenderness, the much more common statin drug side effects. Although the overwhelming majority of our physicians are very aware of the association of muscle pain with statin drug use, few are aware of the possible effects of statin drug use on cognitive functions. When I first experienced Lipitor associated amnesia my reaction was surprise, for in my nearly ten years of clinical use of the early statin drugs in my family practice I had never knowingly encountered cognitive dysfunction. Patients, even less aware of this relationship, are reluctant to report amnesia, confusion and altered memory coming on months or even years after statin drugs are started, thinking it is just old age, an inevitable touch of senility or possibly early Alzheimer's disease. When such patients are brought to the doctor’s office with these complaints, all too frequently the doctor fails to consider the very real possibility that such side effects might be due to their statin drug, the very drug he had placed them on for health maintenance purposes, the very drugs purported to do so much good for public health.
This was the situation in which I found myself almost three years ago after I had experienced my first episode of Lipitor related transient global amnesia. The Lipitor had been prescribed six weeks earlier at the time of my annual astronaut physical at Johnson Space Center. When I returned from my usual walk in the woods that morning, my wife saw me aimlessly walking about the driveway and yard. When she confronted me, I acted confused with no evident recognition of who she was. She reported that I reluctantly accepted cookies and milk but refused to go into our home. I also refused her suggestion to get in the car so we could go to my family doctor. Only after she called the doctor, an old friend of mine, and held the phone to my ear so I could directly hear his strong counsel to get in the car and come to see him did I do so, but only with extreme reluctance. I remembered nothing of the office visit but learned later that my blood sugar was normal at the time and in view of my abnormal mental status, the doctor referred me directly to a consulting neurologist at the nearby hospital.
I seemed to come to my senses somewhat later in the office of the neurologist, which was about six hours after my wife had first noted the onset of the condition. The neurological examination was completely normal except for the amnesia. A MRI was ordered and the neurologist made a tentative diagnosis of transient global amnesia, cause unknown. I had been on Lipitor for six weeks at this time. He saw no relationship and made no recommendations, and shortly thereafter, while still in his office, I felt completely normal. I was even able to drive home but remained totally bewildered by my wife’s description during our drive of how I had spent my day. Three days of uncommon anxiety and agitation followed during which time my mind was racing in a futile search for explanations. Hypoglycemia did not seem a tenable diagnosis, especially since my ingestion of the cookies and milk so wisely offered by my patient wife had no apparent effect on the condition. There was no evidence of head trauma.
I then considered the possibility of electric shock, since as a family doctor I was familiar with this possibility. I had even observed individuals whose heads had inadvertently touched the wire of an electric fence. They had fallen down unconscious only to rise several seconds later and continue their walk, completely oblivious to the fact they had been lying on the ground unconscious only moments before. Focusing on this possibility and using my hiking boot imprints in the soft soil as a guide, I desperately searched the path I had taken on my earlier walk. After spending hours on this project I was unable to find a possibly contributory 'hot' wire servicing a garden, shed or neighboring camp. I questioned neighbors on either side of our home, asking if they had seen me walking along the street during the time in question. One of them who had been working in his garage replied that I walked by his house and had talked with a local woman who also happened to be walking by at the same time. He said I had a face to face conversation with her.
I remembered none of this but, because of two strange marks on my right temple, I next focused on the possibility that I had been touched there by a 'stun' gun. The marks bore a resemblance to the business end of those personal protection electronic gadgets that I had seen advertised in an old U.S. Cavalry catalogue. I imagined myself as having possibly entered the local woman's private 'space' with some off-the-wall word or statement and received a 'touch' on the right temple in rebuff. Such was my emotional state during this time.
Although I had only intuition to go on, no proof, the doctor in me made me suspect the Lipitor, since it was a new medicine for me and this was a new complaint. I stopped the Lipitor on my own and had no further amnesia episodes for the next year. During that time I questioned perhaps a dozen doctors and pharmacists as to any record of Lipitor amnesia, always with a negative response.
Lipitor was again suggested by my NASA doctors at my next astronaut physical a year later. They had not previously encountered any amnesia side effects from this class of drugs and I agreed to restart at one-half the previous dose, five milligrams daily, which is considered a very modest dose by most physicians.
Again, six weeks went by and I experienced my second episode of transient global amnesia. During it's twelve hour span, I seemed to regress in memory back to my teens, precisely recalling details of my high school years, but with no awareness of ever having been a family doctor, astronaut or book writer. My first amnesia episode the previous year had been one of failure to form new memories only, a condition usually referred to as anterograde amnesia. But this episode was startling because, in addition to the expected and usual anterograde element, I experienced retrograde amnesia for my earlier life. During that time I had no recall for my college years and medical school training, my busy and productive years as a USAF flight surgeon involved with space medicine research, my marriage and four children, my selection by NASA as a scientist astronaut, my twenty years as a busy family doctor or my post-retirement years as a writer with eight books to my credit. Many decades of richly lived, richly achieved and richly remembered life were annulled and obliterated from my memory. Only after I regained my senses did I realize the hideous implications of the loss I had sustained during those 12 hours of mind boggling confusion and frustration. According to my wife I had not the slightest recall of medical training or of being a doctor. I knew nothing of my medical practice or of space. The titles of my books, as precious to me as children, were meaningless and had vanished from my mind.
The same doctors who had treated me the year before now made the same diagnosis, transient global amnesia, cause unknown. Again they refused to accept any possibility of a Lipitor association although by now I was finally convinced that Lipitor had caused my problem. But I seemed to be the only one convinced or even suspicious of a relationship. Alone, I remained on very isolated pinnacle where I became both the soapbox speaker and audience, defending my conclusion. Even my wife was ready to accept that any relationship of my amnesia episodes with Lipitor was probably coincidental, hinting that the aging process alone does terrible things to the human body. One can hardly argue with that statement but the doctor in me obstinately saw it differently. These were dark days when despite my conviction, an occasional specter of doubt would reach out momentarily, almost subliminally, suggesting the unthinkable: the possibility of underlying brain disease.
Finally, almost in desperation, I sent an E-mail describing my problem to the Peoples Pharmacy column that is syndicated in newspapers throughout the country. The writers of this column impressed me as being very forward thinking and open to unusual concepts. Their response was very positive and they gave me my first good lead by referring me to a statin drug study at UCSD College of Medicine. I felt a tremendous weight lifted from my shoulders when the principle investigator, Doctor Beatrice Golomb, responded that she knew of several cases just like mine. But the real break came a few days later when Joe and Teresa Graedon of People’s Pharmacy asked me for permission to publish my letter in their column. Of course I said yes and thereby “Let the genie out of the bottle,” as Joe Graedon so colorfully reported to me later. Hundreds of case reports from distraught patients and relatives, and even a few doctors, arrived in People Pharmacy's e-mail and in mine. They described a full array of cognitive side effects from amnesia and severe memory loss to confusion and disorientation, but each had one common thread – all were associated with use of the stronger statin drugs. The one most commonly associated with cognitive side effects was Lipitor, but a few cases were reported from Zocor and Mevacor users as well.
These reports are still coming in. All have been reported to the FDA Medwatch program where they are still in their review process. It has been nearly three years since my first transient global amnesia episode, yet most practicing physicians are still unaware of the cognitive side effect problem associated with the statin drugs. Currently it is all but completely buried in the Physicians Desk Reference’s lengthy list of possible side effects, beyond reach of even the most dedicated physician. Patients on Lipitor should be encouraged to expect, and to report, amnesia attacks, failing memory or increasing confusion. Their statin drug and its dosage should then be the first thing a doctor thinks of, not the last.
Though relatively rare as a side effect, the capricious and unpredictable nature of this theft of a victim’s memory, one's very essence, places Lipitor in a special category. Compared with loss of memory, the other statin drug side effects seem hardly relevant. To be unable to formulate new memory--for whatever length of time--is a thoroughly shattering experience, for the true horror comes later when the amnesia is over and you learn of the mysterious journey you have taken into a world with no past.
Like most doctors and patients in today's world, I had come to regard cholesterol as my personal enemy. Over the past decade of annual astronaut physicals, my doctors at NASA's Johnson Space center had watched the slow but frustratingly steady climb of my total serum cholesterol. Despite participation in regular exercise and constant, almost obsessive adherence to a fat modified, cholesterol restricted diet, my LDL had reached persistently elevated levels and my HDL was borderline low. The time had come for a more aggressive approach.
This same scenario replays constantly in doctors' offices throughout the world. No one had mentioned the significant contributions of cholesterol to the proper functioning of a human body. Cholesterol was just there in the body, a sort of filler. From its prominent notoriety, everyone knew only that it was a major component of atherosclerotic plaques. But how many of us really appreciated the absolutely vital role of cholesterol in our body? Looking back, as a thoroughly experienced physician, I cannot believe how gullible I was in accepting such a superficial explanation. But with both the American Medical Association and the American Heart Association actively promoting rigid cholesterol control, who was I to doubt?
I well recall that as a graduate of medical school in the year 1955 I was early on exposed to the first rumblings of the low fat/low cholesterol juggernaut. Even today I remember it clearly, reverberating down the halls of Walter Reed Army Hospital where I interned, already aware of its progressive molding of my thoughts. While still trying to absorb the newness of it all, I watched incredulously as my physiologist friend, Dr. Bruno Blake, at the USAF School of Aerospace Medicine, poured canned peaches in his corn flakes and wolfed them down after a three mile run. Dr. Balke was one of the first disciples of the cholesterol-modified diet. We joined hands then, nutritionally, for professionally already our 'hands had been joined' by our 'seven-day free floating in water' experiment in 1961. This space flight related 'man in a tub' experiment captured international publicity and a "Today Show" interview. Soon thereafter the first inklings of the Atkins Diet reached everyone's ears and we laughed at how absurd a liberal fat/protein diet seemed. We doctors then were marching lockstep to the music of the low fat/low cholesterol band, brainwashed to a man by the powers that be.
When the professional zeal for Ancel Key's2 low fat, low cholesterol diet became governmental policy, most doctors, myself included, danced happily to the tune. We were thoroughly convinced that the policy was right and equally convinced by our pharmaceutical industry that statin drugs would work safely when diet did not. So the use of statin drugs mushroomed.
When my doctors at NASA determined it was my time for a statin drug, Lipitor was recommended. It was one of the newer, more powerful statin drugs--a class shared by Baycol, Mevacor and Zocor--capable of as much as a 40 percent reduction in total serum cholesterol. As much as a hundred milligram reduction within the first few weeks was reputed to be commonplace. How could I refuse such effectiveness, supposedly with only minimal side effects? If anyone in the medical or pharmaceutical industry had any concerns about the possible consequences of such impressive and abrupt reductions in the level of my serum cholesterol, I certainly was not advised of any of them. Statins were so good they should be put in the drinking water was the most prevalent professional opinion.
As a former military flight surgeon, I have kept a watchful eye on the possible consequences of administrating statin drugs to our flight personnel. Only recently have I learned how much more liberal our medication climate has now become compared to my recollection of my USAF days. If during the medical examination a statin drug is deemed necessary for the control of elevated cholesterol in an otherwise healthy pilot or crewmember, all that is required now are several weeks of 'grounding' initially along with liver function testing at reasonable intervals. No special consideration is being given to the possibility of cognitive side effects because this information is not yet known to those decision makers within the military. These cases and hundreds more just like them have been reported to FDA’s Medwatch and to the pharmaceutical companies' adverse drug reporting system without any action taken to date even though over two years have passed. “The subject still is being reviewed” is their most recent response if they bother to reply at all. The public and our prescribing physicians are still largely unaware of this serious consequence of statin drug treatment. Personally, I think statin drugs should be withheld from military flight personnel until further study demonstrates their complete safety with regard to brain function.

Belatedly, after first-hand experience of one of the devastating side effects of this too-good-to-be-true miracle drug, I am now asking the question, "Just what is the role of cholesterol in the human body and what happens if the metabolic balance of this substance is upset?"
This is a question to which I believe we have found some reasonable answers, answers that will surprise you. We found that the underlying cause of arteriosclerosis is almost certainly due to factors other than cholesterol, the substance of our national focus for the past 30 years. We present compelling evidence that homocysteine may be the real villain, and explain why the past decades of adherence to cholesterol and fat restrictive diets appear to have actually compounded the problem.
The astounding recent progress in diminishing deaths from heart attacks and strokes in this country has been achieved almost completely through technical innovation and surgical intervention. But the prevalence of rampant arteriosclerosis in our bodies has not diminished; it has actually accelerated, belying the claims that high cholesterol is the cause. Real progress in the war on arteriosclerosis will require a much more comprehensive approach than our present misplaced dependence on potent statin drugs with their growing record of completely unpredictable side effects

The Role of Cholesterol in the Human Body
There is no doubt that the present notoriety of cholesterol has all but obscured its physiological importance and necessity in our bodies. Cholesterol is not only the most common organic molecule in our brain, it is also distributed intimately throughout our entire body. It is an essential constituent of the membrane surrounding every cell. The presence of cholesterol in this fatty double layer of the cell wall adjusts the fluid level and rigidity of this membrane to the proper value for both cell stability and function.
Additionally, cholesterol is metabolized into other essential body steroids known as the steroid hormones and is therefore the sole source for the formation of the very powerful chemicals in our body that determine our sexuality, control the reproductive process and make possible our very existence. This same substance that society has been taught to fear happens to be our sole source for androgen, estrogen and progesterone. Researchers marvel at the remarkable similarity in chemical structure these sex hormones have with each other and with the original cholesterol parent from which they were derived. One might say the glaring family resemblance attests to the mighty power of a methyl group here and a carboxyl group there. The destiny of us all is marvelously controlled by such seemingly minor changes.
This same notorious cholesterol substance is also the parent of a pair of steroid hormones called aldosterone and cortisol. They are of adrenal origin and we could not exist without them. Aldosterone protects the body from excessive loss of sodium and water and is known in scientific circles as a mineralocorticoid. It is absolutely vital for life. Without an adequate supply of aldosterone we would be like an ill-prepared desert traveler destined to die of thirst and dehydration under the glaring rays of a merciless sun as water and salt escape from the body. Cortisol is known as a glucocorticoid because of its effect on glucose metabolism, but it also has powerful mineralocorticoid and immune system functions and is fundamentally involved in the biologic response to the stress in our lives. Both of these vital substances are created in the cortex, the outer shell of the adrenal glands. When the adrenal cortex is destroyed by accident, surgery or disease, death is inevitable within days unless another source of aldosterone and cortisol can be substituted. Like the sex hormones mentioned earlier, there can be no aldosterone or cortisol unless an adequate supply of the parent substance, cholesterol, is available. So much of our life is dependent on this remarkable substance.
And where would we be without calcitrol? Another offspring of cholesterol, this remarkable steroid hormone is charged with the responsibility for maintaining the proper level of calcium in our bodies. Just as sodium must be maintained at proper levels for us to function, so must serum calcium be maintained within a very narrow range. Without calcitrol the calcium we ingest would pass through our bowels unclaimed. The calcium in our teeth and bones would be rapidly depleted, leading to advanced osteoporosis, skeletal weakness and fractures. The interference with nerve transmission to our muscles would result in a hyperexcitable state. We have all seen cartoons and movies where a doctor gets an exaggerated knee jerk response while checking a patient’s reflexes. In a state of sufficiently low serum calcium there could result massive seizures of muscles, incompatible with life, in a condition known as generalized tetany. Such is the power of a simple element like calcium on our bodies if homeostatic levels are violated. Proper levels of serum calcium are vital for optimum function of our immune systems and reflect the labyrinthine complex of physiologic inter-relationships as more and more of nature’s secrets are discovered. As we refine our research techniques and microscopes to probe ever more deeply into molecular chemistry, we discover far more mystery, puzzles and questions than we find answers.
Again, cholesterol is the basis of all these steroid hormones without which life, as we know it, would not be possible. But, by no means is the list of cholesterol’s contributions to body function exhausted, for there is another class of cholesterol’s steroid offspring without which our metabolic well-being might be in serious jeopardy: the production of bile acids. Secreted by the liver and stored in the gall bladder these steroids make it possible for us to emulsify fats and other nutrients enabling them to be digested and absorbed as food. In the absence of sufficient bile acids we would all be like those unfortunate souls whose intestinal villi are rudimentary or deficient, which causes them to produce voluminous stools of undigested material while they slowly starve.
The pharmaceutical industry would lead us to believe that rapidly bottoming out our natural cholesterol levels through the use of their highly touted statin drugs is a relatively innocuous process of definite benefit to society. But as we learn more each day of this ubiquitous and unique substance, we must question the veracity of their medical advisors. Cholesterol is perhaps the most important substance in our lives. Researchers everywhere are learning how extraordinarily complex and often surprising are the pathways that produce and metabolize cholesterol in our bodies. Admittedly, even after decades of study of this remarkable chemical, we still have much to learn.
On 9 November 2001 a research news release from the Max Planck Society for the Advancement of Science announced to the world the discovery of the identity of the elusive synaptogenic factor responsible for the development of the highly specialized contact sites between adjacent neurons in the brain known as synapses. Not surprisingly to specialists in the field, the synaptogenic factor was shown to be the notorious substance cholesterol!
The so-called glial cells of the brain, long suspected of providing certain housekeeping functions, were shown to produce their own supply of cholesterol for the specific purpose of providing nerve cells with this vital synaptic component. As many of you may know, the neuronal synapse of the nervous system is the basis of neurotransmission connecting the brain with the rest of the body.
The brain cannot tap the cholesterol supply in the blood, since the lipoproteins that mediate the transport of cholesterol, including both LDL and HDL, are too large to pass the blood-brain barrier. The brain must depend upon its own cholesterol synthesis, which the glial cells provide.
This should be sobering news for those in the pharmaceutical industry developing drugs which interfere with cholesterol synthesis, the mechanism of action of the newer statins. One wonders how anyone knowing the mechanism of brain cholesterol synthesis can seriously challenge the reality of cognitive side effects from statin drug use. The only surprise is that there are not more reported cases of memory impairment, amnesia, confusion and disorientation.
This is heady stuff, indeed, for a substance with such a bad press. When and if the industry finally vindicates cholesterol, it will not be unlike elevating Al Capone to knighthood.

The Modus Operandi of the Statin Drugs
The development of statin drugs was an inevitable phenomenon. After decades of concentrating on cholesterol as the culprit in arteriosclerosis, the pharmaceutical community wasn't about to waste its time and resources looking for
anything except the simplest way to "cut it off at the pass."
The biogenesis of cholesterol starts from a simple chemical reaction: Under the influence of ultraviolet radiation, photosynthetic plants combine water with carbon dioxide, the well known gas we exhale in every breath, to form glucose, the fuel of our bodies. From this humble origin the process of glycolosis converts glucose into the two carbon, building blocks of life known as acetyl-CoA. These simple two-carbon fragments next combine to start the now well-known cholesterol biosynthetic pathway. Three molecules of Acetyl-CoA combine to form the six-carbon hydroxymethyl glutaric acid product known as HMG-CoA, which was proven to be the Achilles heel of cholesterol biosynthesis.
This was the weak point in the chain of events the pharmaceutical industry was looking for and the one which enabled them to develop their statin drugs, for when two molecules of HMG-CoA next combined to form the ubiquitous mevalonic acid, the enzyme, HMG-CoA reductase was required. This enzyme could quite easily be inhibited and suddenly a multibillion-dollar industry was born with the development of the HMG-CoA reductase inhibitors known as the stain drugs. Whether Lipitor, Mevacor, Zocor, Pravachol or the ill-fated Baycol, all use the same mechanism and are merely variations of the same theme as marketed by different pharmaceutical companies to insure market access.
Research biochemists identified the HMG-CoA reductase step as a natural control point for cholesterol synthesis since the reaction was not reversible and it was the slowest step of the entire cholesterol biosynthetic pathway. It seemed a natural for cholesterol control--the pharmaceutical companies now had their "corral." One can almost feel the pulse of industry leaders quicken in anticipation of the potential market size.
One also can imagine the chagrin of the pharmaceutical industry to discover in a simple yeast from the Orient that Mother Nature already had provided her very own “completely natural” HMG- CoA inhibitor, Red Yeast Rice! For thousands of years this yeast has been used to ferment rice into wine and as both a spice and preservative.1 Needless to say, any possible interference of this Oriental fermentation product with our emerging statin drug industry was obviated by Merck’s patent--the first ever filed on a naturally occurring substance. Mother Nature’s cholestin would never compete with Merck’s identical product, Lovastatin, which has the trade name of Mevacor.
Cholesterol, discovered as a major constituent of gallstones, was identified in 1775 as the first known steroid.. The relationship of steroids to the terpenoids was not discovered until the late 1950’s. Since then the modern study of cholesterol has included some of the most creative and productive scientists of the twentieth century. This work continues undiminished today. Scientists marvel at the astonishing efficiency and sheer elegance of the steroid biosynthetic pathway. Its complexity is such as to defy human credulity.
The mevalonic acid-HMG-CoA reductase step is but the first step on the long climb to cholesterol synthesis. Many intermediate steps are required before the ultimate goal of cholesterol synthesis is achieved. In at least two of these steps, five carbon units of the enormous terpene class of drugs, destined to be used for other biosynthetic pathways in the human body, are involved. Statin drugs, while curtailing cholesterol, must inevitably inhibit the production of these vital intermediary products. The pharmaceutical industry has long been attempting to develop a means by which interference with cholesterol production might be achieved farther along the biosynthetic pathway beyond the point where these vital intermediary product originate but up to now have failed. The inevitability of significant, serious and even lethal side effects has been knowingly accepted. Ubiquinone coenzyme production is one of these collaterally damaged areas of great concern since the ramifications are both broad and profound. Biosynthesized in the mitochondria--the tiny powerhouse of the cell that is responsible for cellular respiration and energy--ubiquinone functions as a vital and necessary electron carrier to our ultimate respiratory enzyme, cytochrome oxidase.
Ubiquinone in a slightly altered form known as ubiquinol is found in all membranes where it has a vital function in maintaining membrane integrity. Compromise of this important role is thought to be involved both in muscle cell breakdown and nerve conduction defects associated with statin drug use. Dr. David Gaist2 in a study of 116 patients reported a 16 times greater risk of polyneuropathy among long term statin drug users. This new and very serious side effect of statins should be of special concern to diabetics, many of whom have been prescribed statins because of their high-risk status. All doctors know that a very common outcome of long standing diabetes is peripheral neuropathy. To prescribe statins to these patients because of their special predisposition to heart attack and stroke is a serious decision, a delicate balance of judgment that should be undertaken only after painful soul-searching on the part of the doctor. This is the so-called art of medicine--making the right choice of medicines when considering more than one variable.
This new, sobering information is in addition to the now well-known statin drug associated inflammation of the muscles called myositis and rhabdomyolysis, a condition wherein muscle cells break down and release myoglobin causing secondary blockage of kidney tubules, which may also be based on this loss of membrane integrity. Baycol was removed from the market primarily on the basis of muscle cell damage and breakdown. Unfortunately, many deaths resulted before this corrective action was taken. Deaths still occur because all currently used statin drugs share the myositis and potential rhabdomyolysis side effect of Baycol, although to a lesser degree.
Ubiquinone inhibition secondary to the new class of statin drugs is well known to the pharmaceutical industry, which has toyed with the idea of recommending that supplemental Coenzyme Q10 be used by patients on statins. Although the drug company Merck obtained a patent for the combination of CoQ10 with statins in one prescribed dose, no further action was ever taken on this matter.
Ubiquinone is also vital to the formation of elastin and collagen formation. Tendon and ligament inflammation and rupture have frequently been reported by statin drug users and it is likely that the mechanism of this predisposition to damage is related to some yet unknown compromise of ubiquinine’s role in connective tissue formation.
Science has amassed so much research knowledge that very little remains simple and straightforward, so one ventures cautiously into the murky complexity of another secondary metabolite potentially compromised by statin drug use--that of the dolichols. This is an intricate process of cellular activity that has fascinated researchers for years.
Within each of our cells are miniscule factories of immense complexity. Floating in the cytoplasm is a tubular network of membranes called the endoplasmic reticulum. Proteins manufactured there in response to DNA directives are packaged into transport vesicles that are shuttled across the cytoplasm to the Golgi apparatus. The operation of this marvel of complexity, which only recently has begun to reveal its secrets to research scientists, has been likened to that of a post office. Electron microscopy has revealed that its general structure is comparable to a stack of hotcakes bound by a common membrane. It is here that vesicles of proteins are linked with certain sugars, zip-code fashion, and directed to their final destination within and without the cell, and it is here that the dolichols play their unique role. Without dolichols there would be intracellular chaos as various proteins could not be directed to their proper target and would, in effect, be dead-lettered. The post office analogy, though childishly simple, comes very close to describing the Golgi apparatus function as we understand it today.
In the last decade mankind has received an incredible gift--the gift of DNA mapping--which introduced wave after wave of astonishing new information which promises us the ability to tailor a drug to a patient’s specific needs based upon his or her genome. The reality is that this incredible feat is already here and soon will be commonplace. Not only will we be able to predict with complete confidence which of our available drugs are most effective for a patient’s specific needs, but we also will be able to choose the drug least likely to have serious side effects.
Specific DNA printing is in the very near future but in today’s world, with our ability to predict side effects still in an almost primitive state, we allow much too liberal statin drug use. In properly selected patients the use of such drugs can be life saving, of this there is no doubt. In patients known to have atherosclerotic heart disease, threatened stroke from carotid occlusion, or with high risk for these life-threatening conditions, the statin drugs clearly have an obvious emergency function. But as the zeal for primary prevention by both the pharmaceutical industry and organized medicine serve to promote wider and wider utilization of these powerful drugs, harmful side effects become an immediate, greater concern. The physiological implications of these drugs are profound when based on just what is actually known at this time, but when one adds the reality of our present shallow grasp of physiology at the intracellular level, there is justification for the question, “Do we really know what we are doing?”

CONCLUSION
Transient global amnesia is probably as old as man and statin drugs may be just the latest of its many triggers. However, its varied reactions--vague preservation of identity, maddeningly repetitive questioning, absolute inability to preserve new memories and, in some cases, retrograde memory lapses decades into the past--can be subtle and elusive. But regardless of which trigger provokes an attack--cold water, emotional stress, exercise, sex, cerebral angiography or statin drugs--the psychological impact on the patient is devastating.
And the bottom line is that many statin induced episodes of transient global amnesia need not have happened. Lower initial dosages would have prevented a negative reaction in many cases, particularly in patients receiving Lipitor, the most potent statin, which also has the highest recommended initial doses of all statins. The very real and compelling evidence that cholesterol is not the culprit in some of the diseases now being treated with those unnecessarily high doses of statin drugs cannot be ignored. Add to this the tantalizing possibility that patients with moderate or slightly elevated levels of cholesterol may be better left untreated, at least until more adequate research reveals the full spectrum of statin drug side effects.
Statin drugs, as they currently exist, interfere with cholesterol biosynthesis at the HMG-CoA reductase step and, as a consequence, inevitably must interfere with ubiquinone and dolichol production, processes vital for cell integrity and maintenance. This can only be called collateral damage, a very serious consideration, since most of the side effects we are seeing are secondary to this collateral damage. On the other hand, the absolute requirement for cholesterol’s biosynthesis by the glial cells for synapse formation and function suggests a strong possibility that statin drugs might interfere directly at the brain cell, as well as at the better understood hepatic cell level. Cognitive problems seem almost inevitable with interference at the glial cell level.
In fact, during a March 2003 Texas court testimony,1 an adverse witness, the head of the Bayer Corporation's worldwide regulatory affairs, admitted that brain impairment in their laboratory dogs was one of the toxic side effects of Baycol during their 1995 research. He further testified, "One concern was the toxicity they found in the brain of dogs. But the other was that they had no way to identify this and who might be at risk before it happened so there was no way to detect that someone was at risk for this side effect." The problem was not unique to Baycol, he said, "It was actually shown with the other statins as well." "And I think today no one pays much attention to it."
It is impossible to hide our frustration that now, long after patient case reports first began to surface, the average practicing physician in this country is still completely unaware that serious cognitive side effects can be associated with statin drug use. Many of those reports tell of doctors who all too often jump immediately to the presumptive diagnosis of 'senior moments,' approaching senility or possibly even early Alzheimer's, when apprised of memory gaps and increasing confusion in the patient. Frequently, the last thing considered is a reaction to the patient's statin drug. One of our aims in writing this book and heightening the awareness of both doctors and patients will be realized when doctors first consider statin side effects as the genesis of their bewildered patient's symptoms.
Doctors must also remember that such side effects do not necessarily become apparent only in the first few months of statin therapy. Some of the most serious side effects reported have presented after an interval of three or four trouble-free years of statin use, so constant vigilance is necessary. Patients all too frequently accept erosion of memory and increasing tendency for confusion and disorientation as an inevitable consequence of aging. They, too, often need to be reminded that not all memory problems are age related and that they as well as their doctors must always consider a medication's side effects when cognitive problems appear.
And there are two sides to the cholesterol issue. This notorious, Janus-faced substance is both a component of atherosclerosis and at the same time, one of the most important substances in our body. In its first guise, there is no doubt that cholesterol is a component of atheroma but it is not the cause of the underlying arterial disease. McCulley paved the way--and other researchers are following--when he determined that homocysteine, by allowing lipid/mucoid 'streaks' and inflammatory cells to accumulate in those fragile tissues lining the arteries, is the initial trigger of arteriosclerosis. Cholesterol is a more or less passive bystander, streaming by these damaged areas within its lipoprotein carrier and occasionally deposited by errant LDL, misguided in its alien, 'oxidized' form. Gobbled up by a wandering phagocyte, the complex becomes the ominous 'foam cell' and the process of hardening of the arteries with plaque formation is underway. With or without excess cholesterol the process of arteriosclerosis can and does take place in arteries.
When circumstances mandate control of excessive cholesterol levels--particularly in patients at high risk for stroke or heart attack--and statin drugs are deemed necessary, certain unpleasant, serious and even lethal side effects such as rhabdomyolysis can and should be expected. In addition to the usual side effects of liver and muscle problems associated with statin drug use, we now have knowledge that the previously unrecognized symptom complex of amnesia, memory impairment, confusion, and disorientation can also be present. These cognitive effects mirror an inability to remember who we are and, unfortunately, are not identified as the drug side effects they are. It is very important that physicians make their patients aware of these possible reactions.
The other face of cholesterol in the human body is the vital one and well deserving of the emphasis we have given it. The astounding importance of this ubiquitous substance in synaptic formation and function, so recently discovered by Dr. Pfrieger3 and his colleagues, serves to illustrate just how critical cholesterol is at the cellular level.
Strong statins such as Lipitor, Mevacor and Zocor have the capacity to cause major reductions in serum cholesterol values. Many patients proudly announce that their cholesterol plummeted from “280 to 160” in a matter of weeks, attesting to the spectacular effectiveness of the stronger statins in some patients. However, Dr. Beatrice Golomb, of UCSD's Department of Medicine, reports that in her case studies of transient global amnesia patients,2 cholesterol reductions of this magnitude were very common. Such evidence suggests that abrupt, major decreases of serum cholesterol from statin drug therapy should be taken more as a warning than as an indication of success, for cognitive side effects seemed more likely to occur in these cases. Consideration should be given to prompt reduction in statin drug dosage, followed by more gradual titration to the lowest possible effective dose. The longer even the smaller doses are taken by a patient, however, the more potent they can become, and care must be exercised on an on-going basis to further reduce even maintenance doses if necessary. With all drugs, doctors should prescribe the smallest dose possible that will achieve the desirable goal of reasonable control. Defining reasonable control is not easy, particularly in high-risk patients where death is a possibility.
No one questions the zeal for pursuing low cholesterol levels when life is at stake for high risk patients. But, in light of our present knowledge of cholesterol’s largely passive role in arteriosclerosis and the increasing presence of side effects from the stronger statin drugs, maintaining tight cholesterol control may be counterproductive for many patients in the low to average risk category. This may be particularly true in patients who have no other serious medical issues.
We naturally focused our attention on diet as the shift in scientific thinking toward homocysteine as the cause of arteriosclerosis and the importance of folic acid, B6 and B12 in controlling homocysteine levels in the body became evident. The 'national' low cholesterol/low fat diet has failed not only its original intent to control arteriosclerosis and its consequences, it has actually fueled type 2 diabetes and obesity epidemics in this country. In its race to produce cholesterol and fat conscious products to satisfy that national diet, the food industry has delivered a superabundance of refined carbohydrates and nutrient-depleted foodstuffs that have exacerbated the problem. Instead of healthier, we have become a generation of pathetically 'fattened sheep,' prey to diabetes, stroke, heart attack, and worsening arteriosclerosis.
For these very real dietary reasons, we have stressed the importance of Dr. Kilmer McCully’s research efforts over the past decades and his vision that a very substantial reduction in the prevalence and severity of arteriosclerosis is possible from dietary supplementation alone. Large-scale studies currently underway suggest he is correct. Diet also holds the promise for reversing the rising tide of Type 2 diabetes in adults, a tide that is now also afflicting young children.
Cholesterol is still very much a problem but on a different level, one that requires a dispassionate reassessment of cholesterol control. Just as McCully’s work has been very influential in our research for this book, so can it be a vital resource for the many health organizations in our country that are involved in making dietary decisions. We need new dietary guidelines for the public and the food industry. We need to get back to basics in the field of nutrition. There is reason to believe that a national diet somewhat more liberal in protein and far more restrictive in refined carbohydrates would be a major step forward. A number of excellent dietary guidelines of this type are available but Dr. McCully’s Heart Revolution Diet4 deserves special consideration because of its focus on homocysteine and nutritional deficiencies as the etiologic agents in arteriosclerosis.
And, finally, knowing cholesterol's critical role in brain function and being aware of the dangers that can result when that process is interrupted or circumvented, we are somewhat incredulous that statin drugs are proposed for any patient other than those at very high-risk.
The present trend toward broader and broader use of statin drugs must be re-evaluated in light of the very compelling evidence that lowering cholesterol is not the solution to lowering the devastating effects of arteriosclerosis. There is no better time than now to challenge this national usage trend. The statin drugs are not without risk. Certainly the many deaths from rhabdomyolysis clearly point to serious and unpredictable risk. And these deaths are still occurring, despite the FDA's belated recall of Baycol. The cognitive side effects such as amnesia and memory loss are of particular interest, not only because of the many cases already reported but also for those cases that will never be reported because they are too subtle. They are lost forever in that wasteland of forgotten things in the mind, mistakenly presumed to be part of our heritage of imprecision and the best our memories can do. In other words, it is likely that the reported cognitive events are but the tip of the iceberg in regard to the true incidence of statin 'costs.' Our memories are so important to us that any hint of compromise, particularly from drugs that were prescribed for a totally unrelated medical condition, strikes at the very core of our being.
Because of these considerations we recommend that statin drugs be reserved for those persons who have a high risk of premature death from heart attack or stroke. Though costly in side effects and money, these drugs are all that is available for such patients and, clearly, when deteriorating conditions no longer allow time for diet and other less invasive control measures, the benefits out-weigh the 'costs.' But even in these extreme cases, doctors who ignore the caveat on statin dosage do so at the patient’s peril
Despite the glowing reports statin drugs receive in the press, strong evidence exists that cholesterol levels may not matter. Ravnskov summarizes that statin drug therapy is reported to be almost as effective for women as for men despite the fact that most studies have shown cholesterol not to be a risk factor for women. Additionally the elderly are protected just as much as younger individuals, although all studies have shown that cholesterol is only a weak risk factor, if at all, for men older than fifty. Another result mitigating against a cholesterol explanation for statin effectiveness is the consistent observation that strokes are reduced after statin therapy even though high cholesterol is only a weak risk factor for stroke. Further burying a possible cholesterol effect mechanism for statins is the fact that they protect regardless of whether the patient’s cholesterol is high or low.
Clearly mechanisms other than cholesterol effect must be invoked to explain statin drug effectiveness in strokes and heart attacks. Possibilities include such anti-inflammatory action as platelet inhibition and smooth muscle blockage but this paradoxical action of the statin drugs still remains to be explained. Meanwhile the war against cholesterol continues unabated.
The attending physician, the patient and the drug industry all lose when drug side effects are unacceptable. This irony is particularly true when these side effects include the theft of our most precious commodity, our very memory.

Duane ' Doc' Graveline