THE FOLLOWING ARTICLE APPEARED IN THE

OCTOBER 2000 ISSUE

THE POISON SLEUTHS

DEATH BY LITHIUM

“Good morning doctor. Oh, my God, what are you doing today? You have the dead body of a young man today. What happened to him? Please tell me.”

“Good morning Tarun. The name of this young man is Vinod, and he was 23 years old. He was living alone in his flat, and was working as a steno cum typist in a local private office. Yesterday night one of his friends Sagar gave him a courtesy visit, and handed over a cheese pizza to him, which apparently he had baked at home. He said that he was learning the art of pizza making, and wanted him to taste one of his creations. After about one hour of taking the pizza, Vinod started having some strange symptoms. He was having slurred speech, vomiting, poor coordination, muscle twitching, severe tremors, severe diarrhea, trouble in walking and severe drowsiness. There was some mental confusion too. He called one of his neighbors whom he requested to accompany to the hospital. Vinod also told him how Sagar had delivered him a pizza and how after about one hour of eating that pizza, he had started those symptoms. It is from him, that we have come to know the whole story. He arrived in the hospital at about 11 pm. The doctors tried to arrive at a diagnosis, and till they could discover the cause of his illness, they decided to keep him on conservative treatment. However today morning Vinod died at about 5 am.”

“Oh, that’s terrible. So do you think Sagar mixed something in the pizza to kill Vinod?”

“Could be. I am not sure. But Sagar must have had some motive to kill Vinod. We have gone into the background of Sagar, and have found out that he was a chemistry graduate and passed his M.Sc. examinations in chemistry with flying colors. He got admission in a Ph.D. course too, but dropped off because of some family problems. On deeper probing we found out that both Vinod and Sagar loved a very beautiful girl Sudha. Sudha however had shown an inclination for Vinod and Sagar never liked that. Everyone was aware of this fact, but everyone took it very lightly. Nobody ever thought – nor are they convinced now – that Sagar could kill Vinod because of that. The police has caught Sagar and have asked questions from him. Sagar looks terrified, but he asserts that he did not kill Vinod. It is now up to me to find out how he died.”

“So how did he die doctor?”

“Tarun, from the symptoms that Vinod displayed, I can only think of one poison.”

“Doctor, what is that poison? Please tell me. I am getting curious.”

“Tarun. It could be none other than lithium. But I am trying to confirm it through post-mortem, so that we do not face any trouble in court later on.”

“Lithium? Never thought it could be used as a poison. Looks like we are once again on to one of your great stories on exotic poisons. Please tell me about lithium from the beginning”

“Tarun, Lithium was discovered by the Swedish scientist Johan August Arfwedson (1792-1841) in 1817, who believed it to be a new kind of alkali. Fellow scientist Jöns Jakob Berzelius (1779-1848) suggested that this substance be called “lithia” because it was obtained from the mineral petalite, which was stony in nature. I may tell you that in Greek, the word lithos means stone. This Greek word makes its appearance in many medical terms such as lithotomy, which refers to removal of stone from the urinary bladder. Berzelius perhaps wanted to highlight lithium’s origin from stone (by naming it after the Greek word for stone), because similar elements sodium and potassium had earlier been discovered in plants, and it appeared rather odd to him, that a similar element must now be found in a stony substance. However, later the British chemist Humphry Davy (1778-1829), changed the name to Lithium, which stuck. Well, that is as far as the naming of this element is concerned. Now, as you must be knowing, Lithium is the lightest of all metals (group Ia). Its atomic number is 3, and its molecular weight is 6.941 daltons. It is a soft, silver-white metal having a boiling point of 24480 F (13420 C) and melting point of 3580 F (1810 C). Its specific gravity is 0.534. As I told you earlier, it resembles sodium and potassium quite closely.”

“Doctor has lithium been used as a medicine too?”

“Lithium salts have been used in therapeutics for quite sometime. As early as 200 A.D., the Greek physician Galen was prescribing alkaline spring baths for manic patients. Interestingly lithium is abundant in some alkaline mineral-spring waters. In the 1850s, Lithium salts were used in the treatment of gout. Gout is a painful condition of the joints, in which sodium urate crystals are deposited in the joints. The aim of gout therapy is to somehow remove that excess sodium urate from the joints. When lithium salts are given to such patients, they would react with sodium urate and form lithium urate, which is highly water soluble. It was believed that in this way, it would “wash away” the excess sodium urate stored in the joints. It however proved worthless. In those days gout was believed to include symptoms of mania and depression, and by extension, it can perhaps be said that these salts were used for treating these symptoms as well. However it was later used “exclusively” for the treatment of psychiatric ailments, when in 1880s, John Aulde and Carl Lange observed that lithium could be used to treat symptoms associated with depression, independent of gout. However its use could never “catch on”, because of the serious toxicity associated with it.

In the same era, lithium bromide was used as a sedative and anticonvulsant. Since lithium chloride has a salty taste, it was used as a substitute for sodium chloride, or common salt, in heart patients in the late 1940s. I may tell you that sodium chloride or common salt is strictly prohibited in heart patients, as it is known to increase blood pressure. However substituting lithium chloride for sodium chloride proved disastrous, as many persons suffered from chronic lithium poisoning, and some even died. Its use as a salt substitute was withdrawn immediately thereafter. Interestingly, it has also been used as a constituent of the soft drink 7-Up, which was once very popular in the US.

In 1949, a little known psychiatrist named J.F.J. Cade in Australia “rediscovered” its use in the treatment of some mental disorders. He was looking for toxic nitrogenous substances in the urine of mental patients. He had to inject these substances in guinea pigs and see the effects. In one of the steps of these experiments, he had to administer lithium salts to guinea pigs. He noticed that the animals became lethargic. Cade immediately saw its use in manic patients, and prescribed it to them. It was met with remarkable success. However in the US, the doctors were so skeptical about it (because of earlier deaths of patients taking lithium chloride as salt substitute), that they did not use it till 1970! A case of over cautiousness undoubtedly.”

“Doctor, you have used the terms mania and depression too often. Could you please explain a little bit more about these ?”

“Sure. But let me tell you a little bit about mood disorders first. Mood disorders were earlier known as affective disorders. These are those disorders of the mind in which the mood swings regularly between mania and depression. Mania is a condition where there is extreme excitation, excessive elation, agitation, over talkativeness, flight of ideas, fleeting attention, and sometimes violent, destructive or self-destructive behavior in the patient. Depression of the other hand is a condition where there is an exaggerated feeling of sadness, melancholy, dejection and worthlessness. Mania and depression are thus two “opposite poles” of the mood.

Unipolar disorders of the mood are those in which the mood remains at “one pole” (Latin unus, one) as in major depression. In bipolar psychiatric disorders, the mood cyclically switches between these two poles (Latin bis, two), with the normal symptom free period (called euthymia) between them, which may last for weeks, months or even years. If the patient is passing through a manic phase, his disorder is diagnosed as bipolar disorder, manic and if through a depressed phase, as bipolar disorder, depressed. Patients may have depressive and manic features simultaneously. For instance a patient may have extreme fatigue (a symptom of depression), along with racing thoughts (a symptom of mania). Or he may have hypersomnia (a feature of depression) along with increased sexual drive (a symptom of mania). The disorder of these patients is diagnosed as bipolar disorder, mixed.

Mood disorders are fairly common. It has been estimated that about 5% of the adult population in the US is suffering from clinically significant mood disorders. Interestingly, disability resulting from mood disorders, even those that are minimally symptomatic, exceeds that of most major chronic medical disorders such as diabetes, arthritis and angina. A distinction between unipolar and bipolar disorders is important from a clinical standpoint. It has been seen that bipolar disorders respond better to lithium than unipolar disorders. When given to manic patients who characteristically sleep very little, lithium corrects the sleep disorder as the mania abates.”

“Doctor, have lithium salts been used in other diseases too?”

“Yeah, they have been used in patients who have an abnormally low number of white blood cells in their blood. Lithium has been beneficial in increasing their WBC counts. It has also been used in some types of headaches. Lithium Carbonate is effective in the treatment of thyrotoxicosis (a condition in which the thyroid gland becomes overactive), and provides an alternate therapy when conventional antithyroid drugs can not be used because the patient is allergic to them. And of course the biggest use of lithium salts is in psychiatric conditions as I told you earlier.”

“Doctor how does lithium act to help in psychiatric conditions?”

“Nobody really knows, but there are interesting conjectures. You may be knowing that sodium and potassium, two elements which are very similar to lithium are very intimately connected with passage of nerve impulses. It is believed that lithium “mimics” these elements and in some way, alters the passage of nerve impulses in such ways that the patients of mania become relaxed. There are some other theories too, but they are also conjectural in nature. After Lithium is eaten, it is completely absorbed from the gut in 8 hours, with peak concentrations in plasma occurring in 2-4 hours after an oral dose. Approximately 95% of lithium is excreted in urine, 4% in sweat and 1% in faeces. About 80% of the filtered lithium is reabsorbed in the proximal tubules of the kidney. None is reabsorbed in distal tubules. Elimination half-life is 24 hours, which goes up to 60 hours during chronic lithium treatment. Half life refers to that period in which half of the ingested quantity of lithium is excreted from the body. Lithium is excreted in milk, so mothers taking lithium must not breast-feed their babies.

“Doctor, is lithium available in the market?”

“Oh sure. Lithium is available with the chemists mainly as lithium carbonate (300 mg tables) and as Lithium citrate syrup. The commonly available tablets are Licab (made by Torrent) 300 mg tablets or capsules, and Lithocarb (made by Merck) 300 mg capsules. The therapeutic index of lithium is very low, approaching almost 2-3)....”

“Excuse me for the interruption doctor, but what is therapeutic index?”

“Tarun, almost any drug which can be used as a medicine, can be used as a poison too. But generally for a drug to be used as a poison, it has to be used in really a great quantity. If, a drug is useful clinically in a dose of say, 1mg, it might be poisonous in a dose of 200 g. Thus to be used as a poison, it has to be used in a dose which is 200,000 times the therapeutic dose. Its therapeutic index thus is 200,000 – a very high number. High therapeutic indices show that a drug is quite safe to use. But now let us take the example of another drug. If it was useful clinically in a dose of 1 mg, and toxic in a dose of say, 2 mg, its therapeutic index would be just 2. Doctors would have to use this drug very carefully, because if by mistake they increase the dose just a little, the patient might have serious toxicity.”

“Oh, I see. So the therapeutic index of lithium is just 2 or 3. This is really dangerous.”

“Yeah. In fact, because of its low therapeutic index, plasma lithium concentrations in patients receiving lithium have to be monitored very carefully. Almost every week the plasma lithium concentration may have to be determined and dosage adjusted accordingly. Optimal concentration is supposed to be between 0.8 and 1.25 mEq per liter. This concentration is achieved by 900-1500 mg of lithium carbonate per day or about 3-5 tablets per day. The following table may give some useful figures regarding lithium toxicity.

Thus a total of 20 tables taken at a time may be sufficient to kill a person. I may tell you that Lithium may begin its own vicious cycle of toxicity in a very interesting way. It is known to antagonize the effects of antidiuretic hormone (ADH). This is a hormone, which reduces the formation of urine in the body, and thus preserves water in the body. By antagonizing ADH, the urine output may increase and the patient may become dehydrated. To compensate for this, there may be more tubular reabsorption of water in the proximal tubules, with associated increased reabsorption of lithium, and consequent toxicity.”

“I see. Now I know enough about lithium to follow your conversation. Tell me how Sagar must have killed Vinod.”

“Tarun, while I was talking to you, I was simultaneously determining the amount of lithium in Vinod’s blood, and I have found the concentration to be >5 mEq/L. I feel that Sagar bought some tablets of lithium carbonate or lithium chloride from a chemist, crushed them into fine powder and baked them along with pizza. He gave this pizza to Vinod knowing fully well, that he would die after eating it. He wanted to remove Vinod from his way, so he could marry Sudha. I have chemically examined the remaining piece of pizza found from Vinod’s home too, and have found an excessive quantity of lithium there too. He probably would never have done it for such a minor cause, but he was very sure, he would never be caught, because he used such an ingenious method to kill his rival. But the symptoms of Vinod and some shrewd thinking on my part exposed his plans. Come, let us tell the police that it is Sagar who has poisoned Vinod.”

“That is very clever of you doctor. Without your clever deduction it would have been impossible to say how Vinod died and Sagar may have gone scot-free. What are you going to tell me next time?”

“Tarun, next time, I would tell you about a very interesting poison – Akee.”

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(To protect the identity of the individuals, their names, as well as the various dates of occurrence have been changed)