MASHUP: Aboriginal Smokeless Nicotine, Quinine & Caffeine Therapy, African G6PD Deficiency

Drugs, malaria, colonialism and biological adaptations to parasites

I haven’t written a mixed article in a while, and some smaller topics have built up in my notebook of ‘interesting things’. This time a few thoughts have been rattling around in my head about malaria, iron deficiency and biological adaptations to both dairy and living in the rainforest. Two good threads on Twitter/X recently have helped organise some of my ideas - the first about the Somali phenotype and pastoralism/anemia, and the second about the ‘pseudo-domestication’ of the mosquito by Bantu speakers in the deep past. The bulk of this article is concerned with antimalarial drugs, caffeine and genetic responses to malaria.

First though I want to turn to a lesser-known curiosity - Aboriginal Australian tobacco

My friend Lanius wrote a great piece about the history of tobacco and nicotine in the Americas, and that is where most people think about when they imagine the plant. But Australia and several Polynesian islands also possess species of wild tobacco plant. In the case of Australia it is slightly confusing, since we have multiple plants which contain varying levels of nicotine. The two most important are Duboisia hopwoodii and Nicotiana suaveolens. The Aboriginal term most often used for the preparation of these plants for consumption is pituri, usually a mixture of tobacco plants and wood ash, chewed or kept in the mouth almost like a modern nicotine pouch. Unlike many other wild tobacco plants though, some Australian species contain high levels of nornicotine, which is a far more toxic substance than nicotine.

Duboisia hopwoodii

The earliest records of the plant go back to 1770, when Joseph Banks wrote in his diary:

We observd that some tho but few held constantly in their mouths the leaves of an herb which they chewd as a European does tobacca or an East Indian Betele. What sort of plant it was we had not an opportunity of learning as we never saw any thing but the chaws which they took from their mouths to shew us

The uses of the plant seem to vary. Sources describe people using it for visions, to prevent hunger, to walk long distances, to excite oneself for combat, for medical ailments and just about everything in-between. That sounds familiar to anyone who has used nicotine on a regular basis, its addictive quality means it improves just about every situation.

Curiously the Aboriginal groups who used the plants did not seem to smoke them, which was commonplace everywhere else. Instead they developed a method to incorporate very alkaline wood-ash into a mixture of leaves and broken stems, which helped the nicotine transfer across the skin or the inside of the mouth:

Acacia salicina is one of the plants most preferred for the ash, which Higgin [52] reported contained calcium sulphate at 51%, a 'much larger quantity than in any other ash at present known to us'.

The quid is held in the lower lip and buccal cavity or the cheek for extended periods of time. The oral cavity has a thin epithelium and rich blood supply, consequently the absorption of the nicotine is rapid and avoids first pass metabolism. Nicotine is an alkaloid so the addition of an alkalizing substance such as ash would be expected to raise the pH and therefore reduce its ionisation and increase lipophilicity, which would potentiate both the release of nicotine through the plant cell wall and the absorption through the mucosa of the mouth. The quid is passed from one chewer to another before the owner returns the quid to their own mouth. When not in the mouth, the quid is stored in the post-auricular space (behind the ear) under a breast, or under an arm-band or a head-band [15] - all are sites allowing for the continued absorption of nicotine via the transdermal route, which suggests similarity to the use of a commercial nicotine patch. Furthermore, a final quid is prepared and retained in the buccal cavity overnight, thus there is a potential that exposure and absorption of nicotine for chewers is continuous.

-The pituri story: a review of the historical literature surrounding traditional Australian Aboriginal use of nicotine in Central Australia (2010) Angela Ratsch, Kathryn J Steadman & Fiona Bogossian 

I’ve written before about how nicotine and smoking tobacco have become so synonymous in the medical literature that we don’t really know what the effects of nicotine are without the smoke damage. What studies have been done suggest a suite of benefits to nicotine consumption, and certainly without the smoke the danger decreases dramatically. With this case of Aboriginal pituri tobacco, we have another set of data to incorporate - for example, maternal health before before and after pregnancy gives some interesting results when pituri chewers are considered:

In the study cohort, one chewing participant (5%) was recorded as having elevated blood pressure compared with n = 5 (22%) of the smokers and n = 7 (23%) of the no-tobacco users…

In parallel with the finding of a reduced rate of hypertension in the chewing cohort, the research found only one chewer (5%) with maternal anemia compared with an equi-prevalence of 26% in the no-tobacco users (n = 8) and smokers (n = 6).

The pituri chewers had the lowest rate (14%) of clinically significant post-partum hemorrhage (> 1000 ml) compared with 22% of smokers and 36% of the no-tobacco users

Quinine & Caffeine

Quinine is best known today as the bittering agent in tonic water, but its history and chemistry underpin European colonial expansion across the world, as well as aiding in the development of parasitology and public health. The compound is derived from the bark of the Cinchona plant, which is a large family of trees and shrubs native to South America. 16th century Jesuit missionaries had noticed that the local Quechua people of Ecuador, Peru and Bolivia made use of the powdered bark to cure fevers and muscle trembling. Europe’s introduction to the plant began shortly afterwards, and through royal patronage it began to be employed more widely, particularly in the armies and navies of the great powers. In 1717, Prince Eugene of Savoy’s forces at the Siege of Belgrade were issued with ground cinchona bark; the British Navy was similarly deployed to West Africa at the same time with rations of the drug. British forces in India, in China; Americans, French, Dutch - everyone was dosing their soldiers with cinchona. It worked wonders, despite tasting so vile that its recipients would go to great lengths to avoid taking it.

Cinchona bark

The production and trade of cinchona over the last few hundred years had enough colourful characters and stories to fill several books, as did the hunt for its active component. Peru realised quickly that cinchona was a game-changer, and banned all exports of the plants and especially the seeds. It took a British adventurer and alpaca farmer, Charles Ledger, to smuggle them out and sell them to the Dutch. Java quickly became the world’s epicentre for malarial medicines, producing millions of pounds of bark and attracting aggressive competition as the Netherlands sought to create a cartel over prices. The Second World War saw a catastrophic restriction of these drugs as Japan invaded the islands and archipelagos of the Pacific. The US founded the Cinchona Missions, to seek out new sources of wild cinchona, but soldiers perished like they hadn’t for a century under the ravages of malaria.

Malaria is of course principally caused by the parasite Plasmodium falciparum via the bite of the female Anopheles mosquito. Despite Europeans knowing that cinchona was an effective remedy against the symptoms of malaria, it took a long time to fit the pieces of the puzzle together. Incredibly the first attempts at isolating quinine came in 1790, from the French chemist Antoine François de Fourcroy, quickly followed by efforts in 1811 from the Portuguese navy surgeon Bernardo Antonio Gomes. It wasn’t until the pioneering work of Pierre Joseph Pelletier and Joseph Bienaime Caventou, who discovered (amongst other things) emetine (1817), strychnine (1818), brucine (1819), and veratrine (1919), that the world finally learned the secrets of ‘Peruvian bark’. Quinine was isolated by the forceful duo in 1820, and Pelletier’s colleague - Pierre Jean Robiquet - found the important molecule caffeine a year later. Within a few years quinine was being administered in hospitals across France.

The benefit of discovering quinine was that cinchona bark itself was wildly inconsistent in the quantities of the active compound, and nobody knew how much powdered bark to dose soldiers with. Excessive bark caused cinchonism, which are the toxic effects of too much quinine, including tinnitus and vomiting. Quinine was only part of the puzzle though, and it took another 60 years for the parasitic nature of malaria to be revealed, again by a Frenchman - Medical Assistant Major Alphonse Laveran of the French Army in Algeria. He won a Nobel Prize for his work in 1907. Finally the British doctor and polymath Ronald Ross won his country’s first Nobel Prize in 1920 for the discovery of the malaria-mosquito lifecycle.

Left: quinine, Right: caffeine

Still, despite this incredible work, we don’t really understand how quinine works against the plasmodium. The generally accepted theory is that it stops the parasite from digesting hemoglobin properly, leading to a build-up of heme in the organism, which ultimately kills it. Like many drugs, we have theories and empirical evidence, but the mechanism remains elusive.

Switching tracks to caffeine, we should follow this train of thought about empirical evidence. Back in 1821 Robiquet had discovered caffeine whilst looking for quinine in the coffee plant, since cinchona and the Coffea plant belong to the same family. Alkaloids like theophylline, caffeine and quinine help plants deter unwanted insects, by making the leaves and bark taste unpalatable and chemically attacking certain pests. Curiously caffeine has been somewhat overlooked as a potential antimalarial drug, despite anecdotal evidence from 19th century military doctors about the efficacy of coffee on malaria. Only a handful of papers have ever taken it up as a research topic, one in the early 2000’s looking at the effects of caffeine metabolism in Nigeria, and one recent paper using a mouse model for evidence of caffeine’s antimalarial capacities. To quote the conclusions from these:

Conclusions: Acute Plasmodium falciparum malaria produced significant changes in the disposition of caffeine metabolites. Analysis of concentrations in saliva is a useful non-invasive method for monitoring the kinetics of caffeine and paraxanthine in Nigerians.

-The effects of acute falciparum malaria on the disposition of caffeine and the comparison of saliva and plasma-derived pharmacokinetic parameters in adult Nigerians (2000) O. O. Akinyinka et al.

This study shows that caffeine has potential as an antimalaria agent. The chemosuppression observed for caffeine (administered with a lipid-based formulation for delivery) is quite high and comparable to that of chloroquin particularly when administered twice daily to sustain the plasma concentrations for longer and consequently, increase the exposure of the plasmodium to the caffeine in both suppressive and curative experiments. Caffeine may therefore be considered as a drug for treating malaria within the framework of drug repurposing and also as a compound that can be co-administered with other drugs for better results and in a bid to slow down the incidence of parasite resistance through combination therapy.

-Antimalaria Activity of Caffeine, Orally Administered with a Lipid-Based Formulation in a Murine Model (2023) Olatomide A. Fadare et al.

Could caffeine have always been an antimalarial drug?

I sense there’s a lot more research to be done in this area, tapping into a deep history of how and why humans choose to ingest these alkaloids, and what benefits they might bring. Quinine continues to be used in biomedical research, as does caffeine, since it has all sorts of potent physiological effects, including controlling obesity and mediating serotonin synthesis.

African G6PD Deficiency

Our final topic in this meandering tour of biology and history is the question of African genetic adaptations to malaria - specifically sub-Saharan Africa and specifically glucose-6-phosphate dehydrogenase deficiency (G6PD). But first we must return to a specific point in our quinine story.

The recommended dose of cinchona bark differed from place to place, administrator to general. It was noted that sometimes an especially large dose might cause an unpleasant death - starting with chills, a fever, then rapidly moving to jaundice and the passing of black or dark red urine before expiring. This disorder was dubbed blackwater fever, and the cause is still something of a mystery. Most likely in certain individuals the impact of a large amount of quinine with the malarial parasite causes an autoimmune reaction, whereupon the red blood cells burst and dump hemoglobin into the bloodstream, leading to kidney failure.

During the early 20th century, blackwater fever was the leading medical cause of death in expatriate soldiers and administrators in colonial Africa and some parts of south Asia. The relationship to quinine was not universal, but a series of blackwater fever patients showed that a larger than normal quinine dose usually preceded hemolysis by some hours. During the building of the Panama Canal from 1904–1910, Colonel William Gorgas of the U.S. Army distributed literally tons of quinine, subsequently observing 226 blackwater fever cases from a total worker population of 50,000; it occurred mostly in Spanish and Italian laborers.^18,24 The pathophysiology of blackwater fever was widely studied, but remains poorly understood. Its association with prophylactic quinine meant that very different national policies existed, and different groups of expatriates had fixed ideas about what was or was not the appropriate use of the drug.^1,8,19 Blackwater fever entered the folklore of African expatriates, where besides being greatly feared as supposedly always being lethal, required never moving a blackwater fever patient from his sickbed as this would surely cause immediate death.

-Historical Review: Problematic Malaria Prophylaxis with Quinine (2016) Dennis Shanks

In 1942 the British military in West Africa had a problem. Its soldiers kept dying of blackwater fever. The army decided to try something new - they switched their troops from quinine to one of the first new synthesised antimalarial drugs, atabrine. It worked wonders and the British soldiers stopped coming down with jaundice. But the black African soldiers did not. In fact, they began to deteriorate and instances of blackwater fever increased after they stopped taking quinine. What could be happening here?

G6PD deficiency is a genetic condition which effects around 400 million people worldwide, mostly those from the Mediterranean, Africa, the Middle East and parts of Asia. The lack of the glucose-6-phosphate dehydrogenase enzyme results in red blood cells breaking down too early, leaving sufferers tired, short of breath and jaundiced. Strangely, eating the popular fava bean, the base of Egyptian falafel as well as other important dishes, causes a severe reaction in G6PD deficient people - the glucosides in the bean circulating throughout the body and destroying red blood cells.

One might wonder what this has to do with malaria, but that little plasmodium has had a massive impact on the human genome wherever malaria has been particularly acute. Sub-Saharan Africans possess a suite of blood related disorders that provide them with protection against the parasite, including sickle cell disease, thalassemia and G6PD deficiency. G6PDD comes in a number of variants, such as Mediterranean, Mahidol, Kerala, Chinese-5 and African A-. Nobody really understands how all these variants interact with different medicines, but the list is quite large:

Haemolysis in individuals with G6PD deficiency has been reported to follow therapy with a range of anti-malarial drugs (8-aminoquinolines, including primaquine, tafenoquine and pamaquine), sulphones (dapsone), sulphonamides (such as sulphanilamide, sulphamethoxazole, and mafenide), analgesics (such as aspirin, phenazopyridine, and acetanilide), non-sulpha antibiotics (nalidixic acid, nitrofurantoin, isoniazid, and furazolidone), methylene blue and naphthalene [13]. In addition, haemolysis can also be induced by foods (such as fava beans), henna, and infections (including Hepatitis viruses A or B, cytomegalovirus, pneumonia, and typhoid fever) [13, 14]. Keeping in mind that the clinical evidence linking some of the compounds with haemolysis in G6PD-deficient people is weak, there may be no causal relationship between the compound and the less frequent reactions.

-Review of key knowledge gaps in glucose-6-phosphate dehydrogenase deficiency detection with regard to the safe clinical deployment of 8-aminoquinoline treatment regimens (2013) Lorenz von Seidlein et al.

Therefore our 1943 West African soldiers must have been particularly unlucky, in that their variant meant the new antimalarial was more dangerous than the old quinine. Medicine and ethnicity will always overlap in strange ways.

We’ll finish here, leaving the details of how malaria drove a number of diseases during prehistory and the relationships between parasites, drugs and ethnicity for another time.