Tacrine in the Treatment of Alzheimer's Disease

William K. Summers, MD
Article Type: 
Feature Article
January/February 2000
Volume Number: 
Issue Number: 

ABSTRACT Tacrine (1,2,3,4-tetrahydro-5-aminoacridine, THA, Cognex®) has had an interesting history since its synthesis in Australia as part of the WWII effort. In 1986, it was described in its oral form as a potential treatment for Alzheimer's disease. In 1993, it became the first FDA approved treatment for Alzheimer's, but this was not without controversy, and many practitioners believed the drug was ineffective and hepatotoxic. This review of the literature demonstrates the studies that refuted the effectiveness of tacrine were seriously flawed. The role of lecithin was reviewed in the literature. Fatal and serious hepatotoxicity was found to be minimal (less than 5 in over 300,000 patients). While lecithin appeared to substantially lessen the impact of the benign liver enzyme elevations to tacrine, this reaction, if it occurs, is usually seen within the first twelve weeks of tacrine use or not at all. The article concludes that tacrine, although more difficult to properly dose than its competitor, is safe and effective, and even has some advantages over its competitors for reasons that are documented in the article that follows. One must conclude that more patients with Alzheimer's disease should be treated with this drug, and their clinical course monitored closely by their physicians.

Tacrine (Cognex®) was the first FDA approved drug for the treatment of the memory problems of Alzheimer's disease. Considerable politics surrounded its investigation and approval. This paper will try to address the science versus the myth.


Tacrine (1,2,3,4-tetrahydro-5-aminoacridine or THA) is a planar three ring acridine with minimal substitution of an amino group in the five position. Because of the flat configuration like a frisbee and the high pKa of 10, tacrine has the capacity to slice through cell membranes almost as easily as ethyl alcohol.(1) This property made it unique among the ninety other monoamine acridine analogs developed by Adrian Albert in 1940s.(2) It may explain why the oral dose response curve of tacrine is almost identical to the intravenous dose response curve.(3) Dr. Albert was attempting to find a safe intravenous antiseptic to assist the Australian effort in the Second World War. His efforts were interrupted by the British discovery of penicillin, but he remained intrigued by tacrine because of its unique properties of reversing anesthetic induced sleep.(4,5) Later work demonstrated that this broad spectrum arousal of the central nervous system was due to the reversible acetylcholinesterase inhibition. In the 1950s, tacrine was used experimentally to reverse cholinergic coma in animals. Gershon et al. used tacrine in the 1960s to reverse the effects of phencyclidine like drugs.(5,6)

I first encountered tacrine after properly diagnosing a post-cataractectomy delirium as an anticholinergic syndrome.(7) I used physostigmine to reverse the delirium, but it resulted in projectile emesis, diaphoresis, and EKG changes that were disturbing. I reasoned there must be something better.

Several months spent in the Washington University library showed that tacrine was the ideal agent to reverse anticholinergic syndromes. The most experienced person with the drug was Dr. Sam Gershon. Fortunately, this Australian neuropharmacologist was working less than a mile away from me. Dr. Gershon talked to me several times about tacrine. He was enthusiastic about the safety and efficacy of the drug in his work.

In 1980, my colleagues and I demonstrated that tacrine could practically be used in some overdose comas.(5) Using the logic of a final common pathway, I reasoned that a treatment for acute organic syndrome might have a use in chronic organic brain syndrome.

In 1981, the results of intravenous use of tacrine in Alzheimer patients were published.(8) This paper was supported the cholinergic hypothesis of Alzheimer's disease. In nine of twelve subjects with putative Alzheimer's disease, intravenous tacrine demonstrated a beneficial short term effect. Benefit was best seen by separating the subjects into the stage of illness. In the early stages, instruments such as name memorization lists was able to measure drug effect. In the late stages of dementia, different instruments had to be used. The important point is that tacrine did give a beneficial response in all stages, but that different instruments had to be used.

In 1981, I retired from academic medicine, and entered private practice like my father and grandfather before me. I thought that my colleagues and I had made a contribution. I was saddened to read a year later a poorly designed study about tacrine done.(9) The dose of 10 mg given 16, 6 and 2 hours before memory testing was grossly below known therapeutic range. Five of the ten subjects were advanced dementia. Diagnosis of subjects was unconfirmed. As would be expected these showed no effect. The four measurement scales required a high degree of verbal skill and had an early "floor effect." Lecithin is beneficial when given over 8 gm per day for more than three weeks. In this study, lecithin was given in a massive dose of 60 grams over 16 hours. It was unsurprising that the only positive effect was in the lecithin group with early dementia. By 1984, I noted that this report was so negative that it had discouraged further research on tacrine. So I joined a team of neuropsychiatrists at UCLA, led by the late Art Kling, and began working on tacrine out of my private practice. This two year project was done with FDA approved and registered INDs. Validation of special psychometic tests was an essential part of this project.(10)

On November 13, 1986, our results were published in The New England Journal of Medicine.(11) Many features of this paper are poorly understood to this day. Phase I was an open-label dose finding study on all patients with memory difficulties before the diagnostic studies were done. Twenty-three subjects were rapidly dosed up each day on tacrine until cholinergic side-effects appeared (nausea, emesis, diarrhea, diaphoresis). The dose just below the one leading to toxicity was assumed to be the correct dose. This proved to be correct.(12) The personalized optimal dose ranged from one patient at 75 mg per day (25 mg three times a day) to 200 mg per day (50 mg four times per day). The majority of patients were on 150 mg of tacrine per day.

Phase I demonstrated that tacrine challenge can be used in part to assist in the diagnosis of Alzheimer's disease. Six patients showed no improvement at any dose. In each case the exhaustive diagnostic evaluation showed they did not have Alzheimer's disease. One had profound hypothyroidism and responded to synthroid. Two had normal pressure hydrocephalus, and one responded to surgery. One proved to have amyotrophic lateral sclerosis at autopsy. Two had hypertension and by cranial magnetic resonance scan, extensive periventricular white matter infarcts.

Phase II was a double blind placebo cross-over study. Because the typical elderly patient has other conditions and takes other medications, the double blind placebo cross-over design is ideal for study of Alzheimer's disease patients. Each person serves as their own control. Not using cross-over design actually increases the likelihood of error. Two subjects opened the capsules and could taste the difference in placebo capsule. For their efforts to circumvent the double blind, they were eliminated from further study. Fourteen of the fifteen subjects completing Phase II, demonstrated clear positive tacrine effect.

Phase III was the long term open label study. At the time of The New England Journal of Medicine report the patients had averaged being on tacrine 12.6 months. The subject that did not show improvement in Phase II was not offered Phase III.

Mechanism of Action

Tacrine (Cognex®, THA, 1,2,3,4-tetrahydro-5-aminoacridine) has numerous mechanisms of action. The putative principle mechanism of action for Alzheimer's disease is as a non-competitive reversible acetylcholinesterase inhibitor somewhat selective for action in the central nervous system. But the lesions of Alzheimer's exceed the boundaries of the cholinergic system to include noradrenaline neurotransmitter deficits, serotonin neurotransmitter deficits, decreased vascular perfusion.(13) It may be fortunate that tacrine has a wide variety of actions. Tacrine blocks sodium and potassium channels.(13) It has direct post synaptic muscarinic activity, alters monoamine (serotonin and noradrenaline) uptake, increases the release of 5-HT, noradrenaline, and dopamine; inhibits monoamine oxidase A and B, stimulates cholinergic firing, interacts with N-methyl-d-aspartate-phencyclidine receptors.(13,14)

Two other curious actions of tacrine are not shared by pure anticholinesterase inhibitors such as physostigmine and presumably donepezil (Aricept®). First, Alzheimer's disease is associated with decreased cerebral blood flow.15 Tacrine significantly increases cerebral blood flow in patients who have Alzheimer's disease.(15-17) Second, much has been made of the role of amyloid deposition in the pathology of Alzheimer's disease. Tacrine actually blocks the secretion of Beta amyloid precursor protein.(18) It appears that tacrine is uniquely suited to treat Alzheimer's disease.

Clinical Pharmacokinetics

Tacrine is rapidly absorbed with a bioavailability of between 10 to 30 percent. Ingestion with meals can reduce absorption as much as 40 percent. Tacrine is about 55 percent bound to plasma proteins and has a clinical half life of about 3-6 hours following a single oral dose.(14) There are vast inter-individual differences in the pharmacokinetic parameters of oral tacrine, necessitating personalization of dose.(12,19) The apparent volume of distribution is 182 liters with the mean plasma half-life during terminal elimination phase of 2.5 hours.(14) There has been misreporting that tacrine is metabolized into pharmacologically active 1-0H-tacrine.(20) In fact, tacrine is metabolized to up to seven different products. One of these is a chiral (stereospecific) dextro form of 1-OH-tacrine.(21,22) This form is inactive biologically, and not the equivalent to the Hoechst-Roussel drug 1-OH-tacrine (a levo-stereospecific form).(20)


Studies after our initial favorable report were confusing and often discouraging.(23-29) Yet some studies were favorable and approved the use of tacrine in Alzheimer patients.30-38 Several attempts have been made to summarize and make sense of these data.(13,14,39-41) To date, an explanation of the disparate data has not been adequately explained. Table 1 summarizes salient features of the major studies of tacrine.

Table 1. Principle Studies of Tacrine

The term [Unfavorable Study] as used is exemplified by Molloy et al.(28) They concluded, "THA has no clinically important benefits in Alzheimer's disease and is associated with appreciable toxic effects." The flaws listed in Table 1 show how this erroneous conclusion was reached. The dose of THA (tacrine hydrochloride) was beyond not adequate. The dose [Adequate Tacrine] was wrong. The authors used apparently a single daily dose of 50, 75, or 100 mg for two weeks. In our studies the maximum dose was 50 mg q 6 hours (200 mg/day). Tacrine hydrochloride is not a once a day drug and single doses above 50 mg per day would result in higher toxicity with poorer response to endpoints desired. Many of the subjects "tested" in this study were no doubt toxic with tacrine at the time of testing. In the category of [Personalized Dose], Molloy et al. went to great lengths to find optimal doses for subject. They then disregarded their own findings. They randomly assigned the patients to "eight possible orders of drug and placebo across three sessions." [Rapid Dose Finding] in our studies meant changes in dose every day to three days. For this review any change done in three weeks or less was considered "rapid." The issue is that Alzheimer's is a progressive illness, and changing doses six weeks apart introduces a negative bias. In the case of Molloy et al. the dose changes were two weeks apart. [Staging] is a very important concept. In our initial studies we found that at certain stages certain measuring instruments could be used, that were ineffective measurements at other stages of the illness.(8) Molloy et al. did recruit patients who were Reisberg scale 3-6 (late middle to late stage Alzheimer's) because the staging was not correlated to the testing instruments. [Preselection] can actually correct some design flaws. For example, the studies of Eaggen et al. selected for cases with a MMS from 8-28, then used the Mini-Mental Status exam as a measuring tool.(30,31) Table 1 lists the Molloy subjects as "? Unselected." Although, they used the middle to late stages of the Reisberg scale to select patients, this scale was not used to measure drug effect. Finally the [Instruments Sensitive to Stage] category is related to either staging or preselection by performance on a psychometric test. Molloy's study is fatally flawed because of this. All of their impressive array of test instruments are designed to discern subtle changes in early Alzheimer's disease. Their subjects were middle to late stage Alzheimer's, some of whom had to overcome major tranquilizers, and probable tacrine at toxic doses. These problems of "ceiling and floor effects" of psychometric tests have been addressed elsewhere.(10)

In general, why did so many studies fail to appreciate tacrine's positive effects? Only a limited number of problems can account for adverse outcomes in pharmaceutical studies.

1) The diagnosis is wrong.(39) Inadequate diagnostic evaluation would result in false negative results. The original study, done between 1984-1986, used cranial MRI to rule out non-Alzheimer's disease.(11) Amazingly none of the subsequent studies used this readily available gold standard which has now become even more sophisticated with diffusion-weighted and perfusion-weighted imaging.(42) The original study also challenged all patients with tacrine and did not proceed if there was a negative pharmacologic result and laboratory results pointing to another diagnosis. Diagnosing by pharmacologic challenge is a very powerful tool.(43) Farlow et al. and Davis et al. used this diagnostic technique.(32,37) The use of an enrichment population salvaged otherwise flawed study design.

2) The choice of drug is wrong. An example, would be if tacrine simply was ineffective. Tacrine would be the "wrong drug." Another example, would be if the formulation of a drug is wrong. Thus, some generic drugs are not as biologically active as a brand name drug. The original study used 25 mg capsules of tacrine salt. Cognex®, the FDA approved drug, uses 20 mg tacrine base capsules as being equal to 25 mg of tacrine salt. This leads to some confusion in interpretation. More important, having worked with both formulations, there is a distinct difference in the products that I notice.

3) The dose of the drug is wrong. The original study utilized 25 or 50 mg by mouth three or four times per day on an empty stomach. The typical patient took 50 mg three times a day. Administration of more than 50 mg as a single dose or more frequently than every six hours did not happen. Thus, the studies giving tacrine as a single daily dose up to 100 mg were seriously flawed..(27,28) The studies that had a ceiling dose of "100 mg per day, given in three divided doses (of 25 mg/capsule)" were doomed.(23,25,29) Such a study would at best be expected to show less than 20 percent of cases improved.

4) The measuring tool is wrong. It is possible for a slow man to tie the fastest man in the world in a 100 meter race. This is accomplished by using a calendar, rather than a stop-watch, as a measuring tool. Alzheimer's disease has a huge range of capabilities. In the early years, these patients drive, shop, and cook. Here a proper measuring tool would be a sophisticated list of words to remember. In the end stages, the patient is bedridden and needing total care. In these patients, recognition of loved ones, weight maintenance, cooperation in feeding, and less agitation are end points to be measured. To address this problem, our studies segregated the results by a six part staging tool.(8,10)

The tacrine studies did not segregate the results of the patients by the stage of illness the patient suffered from. Some studies had patients with an entry Mini-mental State Exam (MMSE) of 28 of a possible 30. Here it is hard to see a drug effect because of ceiling effect. Some of the studies had patients with MMSE of less than 12, then used sophisticated word lists as their measure of improvement. Such patients would suffer from a floor effect of the instrument and improvements would not be seen. These problems are addressed elsewhere.(10,36,39)

5) The patient's metabolism is wrong. Here tacrine is absorbed and metabolized in some unusual way. The best solution for this is routine steady state serum tacrine levels. Although tacrine levels have been done by numerous authors, steady state tacrine levels to determine therapeutic doses has not been done in any study to date. It has been determined that the best dose just below that which results in cholinergic side effects (nausea, emesis, diarrhea, diaphoresis) and that this dose is typically in the therapeutic range.(12)

6) The patient studied is the wrong patient. Alzheimer's is a chronic progressive, unremitting illness that frequently occurs in elderly people who have a unique set of other medical problems. To prove short term efficacy, the best model is to allow the patient to serve as their own control where the only medication that changes is the tacrine. This is a double blind placebo cross-over design for a period of up to six weeks in each arm and a minimum ten day washout. To do otherwise would be to risk that the "matched control" is indeed the wrong match.

For long term (greater than 12 weeks) efficacy studies the parallel design study would be sufficient if the size of the sample was large enough to erase the variance of individual differences in patients.

Safety and Adverse Effects

The most frequently reported adverse effect are the cholinergic side effects. In order of frequency these include nausea, emesis, diarrhea, dyspepsia, rhinitis, myalgia, tremor, and excessive urination.(13) Typically the presence of these side effects indicates the dose of tacrine is too high. Lowering the dose not only resolves the side effects but also improves memory function.

"Hepatotoxicity" has been publicized, but is a red herring. Studies have shown that this is benign hepatic reaction which is self resolving on discontinuation of tacrine.(44,45) Rechallenge with tacrine who had liver enzymes greater than three times the upper limit of normal was successful in almost 90 percent of cases.(45)

Tacrine has now been used as a daily use drug by over 300,000 patients world wide. Deaths possibly related to tacrine are less than five.(46) In these cases, the patients were frail elderly on other medications, so the role of tacrine was uncertain. Further, Alzheimer's is a fatal illness with an average time from diagnosis to death of under four years. Many cancer chemotherapy agents are far more dangerous. Nevertheless, it is prudent to monitor liver enzymes in the window of highest risk, which is between the fourth and tenth week of initial administration. Additionally, it would be helpful to do liver enzymes within two weeks of other drugs known to cause benign hepatic reactions. Dilantin and phenothiazines are examples of such drugs.

The role of lecithin (phosphatidylcholine) in our studies has been largely misinterpreted. Most of the authors cited in this review appear to believe the role of lecithin is to enhance tacrine's beneficial effect on memory. Although this is true, it was not the principle reason to utilize lecithin. In the 1940s, lecithin was used in severe alcoholics to ameliorate liver damage. Thus, it was reasoned that lecithin would be helpful in prevention of hepatotoxicity associated with aminoacridine compounds. Table 2 relates the frequency of liver enzyme elevations in studies subsequent to ours to the use of lecithin. Two studies which did not clearly show lecithin effect on liver used poor methodology.(28,29) This certainly suggests that lecithin should be used with tacrine for this purpose.

A final reason for utilizing lecithin is the theory that auto-cannibalism of cholinergic nerves can be induced by chronic administration of acetylcholinesterases such as tacrine.(47,48)

Table 2. Relation of Lecithin to Hepatotoxicity


Tacrine is the first FDA approved drug for the treatment of Alzheimer's disease as safe and effective. The fear of toxicity has been exaggerated. Liver function testing could be limited to a window between four to six weeks of initial use or upon addition of other know hepatotoxic agents. Addition of lecithin appears to reduce the severity of benign hepatic reaction. This review shows that the usefulness of tacrine might be underestimated. Dosage should be individualized. Because of the narrow therapeutic window, optimal dose should be confirmed by serum tacrine levels. Usefulness of tacrine can be seen in all stages of Alzheimer's disease. In the early stages, sophisticated word lists can be memorized. In the end stages, the patient is more cooperative with care givers and recognizes loved ones, not by name but as having special meaning to them.


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37. Davis KL, Thal LJ, Gamzu ER, Davis CS, Woolson RF, Gracon SI, Drachman DA, Schneider LWS, Whitehouse PJ, Hoover TM, Morris JC, Kawas CH, Knopman DS, Earl NL, Kumar V, Doody RS. A double -blind placebo controlled multicenter study of tacrine for Alzheimer's disease. The Tacrine Collaborative Study Group. N Engl J Med 1992;327:1253-1259.
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43. Sattin A, Muhoberac BB, Aprison MH, Schauf CL. Tetrahydroaminoacridine (THA) as a pharmacological probe in Alzheimer's disease and other neurodegenerative disorders. Med Hypoth 1989;29:155-159.
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Dr. Summers is a psychiatrist in Albuquerque, New Mexico. E-mail: aca@rt66.com. * He is the original inventor and patent holder for tacrine and has licensed the patent to Warner-Lambert/Parke-Davis.

Originally published in the January/February 2000 issue of the Medical Sentinel. Copyright ©2000 Association of American Physicians and Surgeons.

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