The Strange History of Lariam

Editorial Note: This is the second part of a Lariam Odyssey by Dr Sam Ramsay Smith. The first part ran last week – Lariam Hell.

Like most good stories this one involves expediency, hegemony, immorality, greed and even scientific bias, blindness and dishonesty all in the quest for power and money at the national and international levels. At the personal level there is a range of human disasters from simple depression through loss of job and self-esteem to broken families, unpredictable, inexplicable suicide and other forms of violence. All for the sake of enjoying a malaria-free holiday in the sun.

You can find more on Wikipedia and in The Proceedings of the Royal Society of Medicine, London, April 2007, Vol 100, No.4, pp 170 – 174.

Malaria

Malaria is caused by the Plasmodium protozoon. There used to be only 4 species of Plasmodium when I was roaming Africa from the ‘60s to the ‘80s, but now there is a fifth, Pl. Knowlesi. Of all these virulent parasites which collectively cause millions of deaths every year across the world, the most prevalent and the most dangerously resistant is Plasmodium Falciparum.

In 1975, whilst spending another 6 months in the jungle hospital at Ebolowa, Cameroun, I was gifted a week at the Pasteur Institute in Yaounde to study malaria. The chef de laboratoire was Jacques, a huge, jolly Camerounian malaria technician whose whole life was Plasmodium. He had spent a year at the Pasteur in Paris, truly a centre of world excellence in Tropical Medicine. He was a natural teacher. I learned a huge amount from him, from parasitology to the microscopic interpretation of Plasmodium species, including staining techniques and the clinical management of malaria.

Sometimes the correct treatment depended on identifying the particular species, since Chloroquine was then still active against some of the species. But since 1957 Falciparum was becoming increasingly resistant and it was the one which really killed people through renal failure most often. As the renal tubules became blocked with a mixture of parasites and damaged blood cells, the urine output diminished and its colour darkened, leading to the much-dreaded ‘ blackwater fever’ when the urine turned dark red-black, and almost inevitable death soon followed. There were never any facilities for renal dialysis in the hospitals where I worked in those days.

The final months of the Second World War were fought in malaria-endemic zones all over Asia and the Far East. Whole armies suffered from malaria. Which is why Dr.Ken Goodwin was shooting himself up with mepacrine down in the basement of the Wellcome Museum in 1944, and going yellow with it. There was a desperate rush on in various countries, both Allied and Axis, to develop an appropriate drug to combat this virulent disease which could defeat any army. This desperate need was the justification for mepacrine’s use in spite of its known side-effects.

The birth of Lariam

As increasingly resistant strains of Plasmodium began developing in the Far East from the 1950s, there was a continual search for new active compounds. In 1985 in tropical medicine centres the hunt began for some form of vaccine against malaria but that was years away yet. During the 1960s and 1970s huge resources went into anti-malarials.

The Experimental Therapeutics Division of the Walter Reed Army Institute of Research (WRAIR) lies in Washington D.C.. It was there in 1970 that mefloquine was developed. It was number 142,490 of over 500,000 chemical compounds investigated by the United States Armed Forces to combat the devastating consequences of malaria in Vietnam. It was coded number WR 431,000.

Fighting its colonial wars within the equatorial belt over decades had caused enormous damage to the American forces. Not just the 55,000 lives lost in battle in Vietnam during the 1960s, but also the toll of malaria from Korea to Cuba and the jungles of Vietnam and Cambodia. It had not been that much different during the Crimean War over a century before where a bacilliary plague laid half the armies low. A war could be lost because of a single germ and Plasmodium is a really nasty germ.

The tourist army

The justification for mepacrine and mefloquine (Lariam) more than 30 years later were the same. But then the Vietnam war came to an end. All of a sudden, the US had no serious conflict with unbelievers in global capitalism in foreign parts.

But in this new world, there arose a potential to make profits from its sale to a travelling public around the world. In 1970 the idea of global tourism was in its infancy, but places like Kenya already had an embryonic but growing tourist industry based on its wildlife and it would not take any astute pharma director long to appreciate the value that a good prophylactic anti-malarial might have in the future, which is how Lariam appeared on the market during the 1980s.

Once the tourist potential of Lariam was recognised, preparations were made to develop it commercially. However, Congress dictated that the Armed Forces could not engage in any financial dealings directly with private industry, so a deal was enacted between the Armed Forces through the Walter Reed Research Institute and a major pharma company, Roche.

In order to avoid medical disasters all drugs are submitted to 3 levels of trial – Phases I and II – which take the drug from the laboratory bench and into animal testing. If testing at this level continues to show promise, the testing advances into the final Phase III which specifically determines the efficacy, tolerance and toxicity of the drug in human beings.

The most important investigatory tool used to validate these results is known as the Randomised Controlled Trial (RCT) and is the benchmark for any serious scientific investigation. This phase of testing is often the end of a promising drug.

The missing trials

When the American Army handed over mefloquine to Roche they gave the company all the results of their Phase I and Phase II trials. Shortly afterwards the Federal Drug Administration (FDA) licensed mefloquine for sale in the United States as a prophylactic anti-malarial.

However, it now appears that at no stage were any Phase III trials performed nor any such results presented to the FDA before they gave mefloquine a licence.

This must be a very rare event, if it is true.

If this is indeed true, then somewhere between the government of the USA and Roche there exists a huge ongoing moral responsibility for the care of the many patients damaged by Lariam.

Raising concerns

From the day it was released to the public there have been problems with Lariam. But at that time there was no mechanism to collate any adverse side effects. However, there do now exist various international agencies which perform global drug surveillance and it was following their findings that in 1992 the World Health Organisation issued warnings. In 1992 the United Nations banned the use of Lariam for their armed forces during the war in Cambodia. In 1995 the Civil Aviation Authority banned its use in any of its crew flight members.

In spite of the growing mass of evidence against Lariam and the proactive responses of some organisations who did fear the possible consequences of psychotic changes following the administration of Lariam, it took another 6 years before any serious attempt was made to scientifically evaluate the clinical side-effects of this drug.

The first randomised controlled trial on Lariam was not performed until 2001, by which time it had been on sale to the public for over 10 years, and the results were both significant and startling.

In the first trial, 67% reported significant side-effects, and of these 6% were graded as severe. Most were neuropsychiatric disturbances. But there was also evidence of cardiovascular problems such as arrhythmias, and there are now several recorded cases of sudden death causally associated with Lariam, apart from suicide.

It is interesting that an authoritative article in the British Medical Journal of 2006 on the current available treatments for malaria did not even mention Lariam, but it has taken a further 7 years for the USA to accept it has made a grave mistake, and remove Lariam from the shelves of all its Army pharmacies.

Compensation?

Meanwhile, soldiers from America to Australia are now beginning to sue their governments for subjecting them to this toxic drug. Some of their accounts are heart-rending. These come from some of the toughest and fittest people in the land. The question of compliance was never much an issue within the Armed Forces, as any refusal to take Lariam was treated as Refusal to Comply with An Order and was severely punished.

No one will ever know how many cases of Post Traumatic Stress Disorder, or even Gulf War Syndrome were influenced by the effects of Lariam, but there could be many.

We are left with the certain fact that Roche passively allowed an unintentional, longitudinal study into the after-effects of their anti-malarial drug Lariam, rather than funding any form of RCT. Also, there was never any systematic collection of data at this time, and in the meanwhile healthy young men were jumping off cliffs or stabbing themselves and their wives to death for no apparent reason. The heart-breaking accounts from some of the wives has been an equal motivator for me in exploring this macabre tale of the pharmaceutical industry and big government.

Medicins sans frontiers – doctors without borders

When I arrived back in Amsterdam in January 2007 after my second mission to the Ivory Coast with MSF, arriving in front of my medical chief, I asked 2 questions:

• how many reports do you have concerning the side-effects of Lariam?
• which specific side-effects have been encountered ?

To this day I have had no satisfactory response, in spite of the fact that I now know that several of my fellow MSF colleagues also suffered significant side-effects from Lariam. As a global player in the NGO stakes these days, MSF has a serious responsibility as a medical charity to help clarify these misty areas, and they are in a unique position to do so.

How many MSF volunteers like myself experienced any cardiovascular or neuropsychiatric symptoms following Lariam? Hundreds, if not thousands of mostly young and talented people from every country of the world volunteer to work with MSF. Those responsible for administering that risky journey we volunteers make have a responsibility to protect their workers in every way possible from the effects of war, famine and disease. This should include a well-prepared pathway for the reception of any concern by any volunteer regarding drugs they have been advised or prescribed by MSF.

Questions in search of an answer

• Can we find out why there were no Phase 3 trials on Lariam?
• Has FDA ever given any other licence like this ?
• Could the psychotic and depressive effects of Lariam play a part in PTSD in the military?
• What responsibility would MSF or other NGOs have in this case of disabilities in their volunteers?