Evidence for Self-Medication

Juan J. Villalba and Serge Y. Landau. 2012. Host behavior, environment and ability to self-medicate. Small Ruminant Research 103:50–59

If you’d like to read the article above, but it’s a bit too technical and full of jargon, I’ve provided the gist of the paper below. However, if you’re unfamiliar with the word homeostasis, you’ll need to learn its meaning. I can’t come up with a synonym for it.

Homeostasis - (1) The tendency of an organism or a cell to regulate its internal conditions, usually by a system of feedback controls, to stabilize health and functioning, regardless of the outside changing conditions;  (2) The ability of the body or a cell to seek and maintain a condition of equilibrium or stability within its internal environment when dealing with external changes.

1. Introduction
Animals adapt to changes in their environment and bodies not only through physiology changes that correct for deviation from homeostasis, but also by engaging in certain behaviors (behavioral homeostasis). Thus, a behavior like selecting a food containing a needed nutrient is no different than the secretion of insulin from the pancreas in response to rising blood sugar levels: both responses restore homeostasis. Behavioral homeostasis has been shown experimentally. Livestock modify their intake and diet selection to rectify nutritional imbalances. Besides balancing nutrient intake, herbivores are faced with other challenges such as disease. If behavioral homeostasis exists, then sick animals should self-medicate with substances that restore their health, even the substances contain no nutrients or could be potentially toxic at high levels like plant secondary compounds.

Parasitism is one of the greatest disease problems in grazing livestock. Controlling parasites with drugs is challenging, particularly in recent times due to the rise in drug-resistant internal parasites. Evidence suggests that parasitized apes use natural plant secondary compounds (PSC) as anti-parasitic agents. Can parasitized domestic sheep and goats also learn to use PSC? If the answer is yes, they could learn to self-medicate with PSCs and eat PSC-rich vegetation, either on rangeland or pasture, when needed, while having other nutritious and safe forages available to meet their nutritional requirements.

The objective of this review is to assess the ability of parasitized farm animals to exhibit self-medication behavior.

2. Self-medication and Adaptability to the Environment
In this section the authors argue that animals can adapt to changing environments by balancing their diet as plants change in nutrients and defensive chemicals throughout the growing season. There are many, many studies that support this idea.

3. Self-medication in the Wild
The term “self medication” comes from human medicine. It is defined as “The consumption of a substance, without physician input, to compensate for any medical or psychological condition.” This infers that the patient has the ability to sense an ailment independently and take action to alleviate the ailment. In other words, taking a drug – a non-nutritious, often unpalatable substance – is a special behavior that individuals will exhibit only as a response to illness.
Wild animals apparently use medicinal herbs to treat illness. Unfortunately, the information available on self-medicative behavior in wild species is often anecdotal. Controlled experiments in the wild may be constrained by animal welfare and preservation issues.

Several approaches have been taken to gain reliable knowledge. For instance, based on his studies on primates, Huffman defined a set of conditions to separate self-medication from normal feeding in the wild: (1) the animal should show signs of illness; (2) it should seek a substance that is not part of its normal diet and has no nutritional value; (3) the animal’s health should improve; (4) laboratory analysis of the substance should establish that enough active ingredients have been ingested to bring about the changes observed.

All the conditions listed above have been demonstrated for wild chimpanzees infected with internal parasites. Chimpanzees suffering from parasite-related diseases eat the bitter pith of the plant Vernonia amygdalina, which contain anti-parasitic compounds and is eaten by chimps at doses high enough to combat parasites.

Other plants selected by chimpanzees have medicinal effects to combat internal parasite at the doses commonly consumed:

1.    Limonoids in Trichilia rubescens have antimalarial activity;
2.    Thiarubines in Aspilia species have anti-parasitic and antibiotic properties;
3.    Methoxypsoralen in Ficus exasperata is a strong antibiotic.

4. Methodology of Self-medication Studies

4.1. Observation of sick and healthy animals to demonstrate self-medication behaviors
The studies on self-medication to combat parasites in animals can be sorted into two main categories: 1) observations by pastoralists on domestic animals and by zoologists on wildlife and 2) controlled studies.

A study by Gradé and others was based on a survey of 24 traditional healers and 123 pastoralists in Uganda. Eight plant species were identified as medicinal. These surveys enable researchers to analyze the behaviors of animals in their natural system. However, a look at the data shows the complexity of analysis needed to demonstrate self-medication.

Consuming Albizia anthelmintica was reported in 48 out of 147 animals characterized as suffering from disease. These diseases were identified and placed in the following categories: internal parasites (n = 13), tick infestation (n = 6), heartwater (n = 5), East Coast Fever (n = 4), goat mange (n = 3), rinderpest, lice, tetany, anaplasmosis, contagious bovine pleuropneumonia, scabies, and other ailments. Browsing the anti-parasitic plant, A. anthelmintica by goats was followed by expulsion of worms in the feces and emerged as self-medication procedure with very high level of consensus.

But the effectiveness of A. anthelmintica could be assessed visually only for one ailment: internal parasites. Plant species belonging to the Meliacea family are also said to have multiple effects and are effective against gastro-intestinal nematodes and coccidia, blood trypanosomes, and ticks.
Unfortunately, the dualistic Western concept of illness (one factor, one ailment) is not shared by African rural dwellers. They consider sickness as alteration of body and soul and devise their treatments accordingly.

Another possible flaw of the observation method is that ingestion is observed qualitatively, but not quantitatively. In other words, one cannot evaluate precisely the dose of the anti-parasitic drug ingested, and ensure whether or not the intake of the plant has a medicinal value.

4.2. Controlled studies of self-medication
The evidence presented in the previous section is based upon an association between an observed behavior and a certain outcome such as health improvement. Demonstrations of self-medication in parasitized domestic animals using the scientific method are few. Publications to date involve only sheep as host and gastro-intestinal nematodes as parasite. These two studies were carried out on naturally parasitized animals, of which half were de-parasitized to serve as controls.

However, a better procedure should typically encompass four experimental phases.
Phase 1: Non-parasitized animals are offered forages with and without PSC effective against the targeted parasite. Preferences of forages and their intake are recorded.
Phase 2: Experimental animals are infected with parasites so that the level of individual infestation is known and can be monitored. At the peak of infection, animals are conditioned to experience the benefits of medicinal, as opposed to non-medicinal forage. Forages are offered in a sequence of feeding periods where only one of the forages is offered at a time.
Phase 3: Preference tests are conducted in the parasitized animals. Comparisons of preferences between phases 1 and 3 within individuals enable to establish whether or not infection with parasites is associated with increased preference and intake of the medicinal forage.
Phase 4: Animals are de-parasitized and preference tests are re-conducted.

According to the self-medication hypothesis, preferences in phases 1 and 4 should be similar. However there are problems using this experimental process:

  1. To record individual intake of the PSC, animals must be kept in individual pens for long periods.
  2. In the case of nematodes, peak of infection may trigger an immune response by the animal, which reduces the parasite burden and confounds the amounts of PSC ingested by the animal.
  3. The length of the host-parasite association may be too short to encompass all the phases of the experimental procedure described above. For instance, adult female multi-host ticks stay on farm animals less than two weeks.
  4. The complexity of foraging behavior is very much simplified compared with natural grazing.
  5. In addition, any feeding bout by free-ranging herbivores may include several plant species making the specific association between medicinal plants and antiparasitic effects more difficult.

5. Some Antiparasitic Medicines Found in Nature

5.1. Gastro-intestinal parasites

5.1.1. anthelmintics: Considerable attention has been given recently to the anthelmintic (deworming) properties of PSCs with emphasis on tannins in plants consumed by livestock. However, plant-derived alkaloids and terpenes also have anti-parasitic properties.
Livestock feeding on tannin-containing herbaceous species such as sulla, sainfoin, and Sericea lespedeza or browse, such as heather, a number of acacia species, and lentisk, have lower fecal egg counts than those eating plants of similar quality, or the same rations without tannins. Tannins impair larval establishment and decreases reproduction of internal parasites.

5.1.2. coccidiostatics: Substituting concentrates with cassava hay – containing 13% HCN – resulted in impressive reduction of Eimeria oocysts excretion in Vietnamese goats. Coccidiosis is also alleviated in goats when they eat the fruits of Melia azedarach that contain both tannins and limonoids.

5.2. Ecto-parasites
Neem extract reduces feeding activity of the tick larvae and reduces molting by 60%. When lambs infected with ticks eat azadirachtin, a neem limonoid, in sufficient amounts, it reaches the peripheral blood, decreasing blood feeding by ticks, and often kills egg-laying ticks after detachment.

5.3. Blood parasites
Alcohol extracts of neem tree bark (Meliaceae) reduce blood parasites in rats.

Limonoids in T. rubescens have antimalarial activity in chimpanzees. Furthermore, chimpanzees may eat soils to enhance the biological actions of T. rubescens. They ingest a certain soil shortly before or after eating T. rubescens. This particular soil (dominated by kaolinite) improves the anti-malarial activity of T. rubescens when eaten together.

Lastly, repeated sampling of the bitter-tasting anti-malarial agent chloroquine by malaria-infected mice reduced blood parasite and death in these animals.

6. Evidence that herbivores are aware of their parasitic burdens
The first step of self-medication should be that an animal “shows” signs of illness such as diarrhea, high body temperature, passivity, and so on. Thus, parasitism causes illness and obvious signs of disease. Nevertheless, subclinical parasitism can also challenge the  infected animal by reducing production, even when no signs of the infections are observed. In both cases it is likely animals are aware of the negative impacts of parasites on their bodies. Therefore, we define animal sensing or awareness of sickness as the first stage of self-medication behavior.

6.1. Endo-parasites
The most significant effect of gastrointestinal parasites on herbivores is a depression in food intake, which varies from 6% to 50% depending on the nutrients in the diet. Anorexia may result from pain and discomfort from parasites or a consequence of hormonal changes due to disruption in the gastrointestinal tract. Thus, anorexia is one of the first signs suggesting herbivores sense their parasitic burdens.

Gastrointestinal parasites also impair protein metabolism. Worms cause damage to the lining of the gastrointestinal tract, which causes increased plasma leakage and sloughing of protein from the bowel. Parasitized animals also rely on their immune system to fight parasites and activating the immune system costly in terms of protein metabolism.

Infusions of casein (milk protein) into the stomach improve the rate of protein retention of parasitized animals. Lambs infected with larvae of Trichostrongylus colubriformis and given a choice between two foods with different protein contents, increase intake of protein-rich foods, which may help counter the losses of protein due to parasitism. Parasitized animals grazing a mixed grass-clover pasture increase the proportion of N-rich clover in their diet relative to non-parasitized sheep. Thus, herbivores may also sense a parasitic infection through their increased need for protein.

Internal parasites may also disrupt absorption and retention of other nutrients besides nitrogen such as minerals and vitamins. For instance, helminths interfere with the absorption of vitamin B12 and enhance Co deficiencies, which could also trigger signals that an herbivore is infected with internal parasitic. Toxins produced by internal parasites may also help the animal sense parasitism. For instance, parasite-derived molecules can activate some cytokines, which in turn negatively impact cells and their metabolism in the host animal.

When parasitized herbivores are faced with a choice between manure-contaminated and non-contaminated areas in a pasture, they avoid manure-contaminated areas. Non-parasitized animals avoid manure as well, but this behavior is exaggerated in parasitized animals. Avoidance occurs even when parasite-rich pastures are high nutrients. When infected animals are forced to graze contaminated pastures they graze further from the soil surface than non-parasitized animals thus minimizing parasite intake. Horses grazing in highly stocked pastures exhibit a “latrine behavior”, whereas horses grazing on rangelands, where the parasite risk is lower, defecate randomly while grazing.

6.2. External parasites
The salivary glands of ticks secrete molecules to decrease the ability of the host sensing the infestation. Many species of wild cattle live in tick-infested areas, but tick loads are usually kept to very low levels, primarily by frequent self-grooming. Do ticks trigger self-grooming, inferring that cattle are able to identify infestations? Ample evidence from many studies on antelope in Africa strongly supports the idea that grooming bouts occur in response to an internal cue that initiates grooming bouts at periodic intervals, resulting in removal of ticks before they attach and begin to feed. However, an increased exposure to ticks is also associated with increased grooming. The trigger for grooming may be histamine or the absorption of tick saliva released at biting. In other words, herbivores are aware of their tick burdens, although this awareness explains only a small part of their grooming behavior. The larger the herbivore, the less frequent are grooming bouts. Animals are well able to sense the presence of fleas, but grooming activity may be too energy-expensive to combat fleas.

Collectively, the information above suggests herbivores are “aware” of the presence of parasites infecting their bodies. If herbivores are able to sense their parasitic burdens and if there are anti-parasitic substances in plants, which can potentially provide relief, then parasitized animals should increase their preference for such plants relative to healthy animals.

7. Evidence that infected herbivores increase preference for plant secondary compounds
Besides being aware of their parasitic burdens, a second step of self-medication is that after eating or using a certain medicinal plant, herbivores should experience relief from the upset or discomfort caused by the parasites. Animals are more likely to learn about the benefits of a medicine when they experience illness or discomfort and then experience a medicine that leads to recovery.

7.1 Gastrointestinal parasites
In a controlled experiment, lambs with parasites ate more of a supplement containing tannins than non-parasitized animals, even when the supplement was very low nutrients. In contrast, lambs without parasites ate more of the supplement without tannins than parasitized lambs.

In another study, lambs with and without parasites were given a choice of alfalfa and alfalfa mixed with 10% tannin. Lambs with parasites had a greater preference for alfalfa with tannins than lambs without parasites. These differences in preference did not exist before lambs with parasites experienced the positive effects of tannins or later after parasites were removed with drugs.

When lambs were infected with H. contortus to a much greater degree than natural infections, preferences for a food with tannin were much greater than preferences by lambs with natural infections. Consistent with this, parasitized goats in Spain increased the percentage of tannin-containing heather in their diet relative to goats that had been dewormed with drugs. In Uganda, parasitized goats selectively browse A. anthelmintica (a bitter plant) that leads to declines in fecal egg counts. Sheep with H. contortus ate more of the tannin-rich plant L. latisiliquum than non-infected animals.

These studies suggest herbivores are able to detect the presence of internal parasites and increase intake of a therapeutic plant or food as needed. When need for the therapeutic plant declines due to reduction in parasite numbers, preference for the plant also declines.

Animals unfamiliar with the anti-parasitic effects of tannins do not prefer tannins. However, when animals eat tannins during an infection, preference for tannins increases. Suggesting that the increased preference for a PSC during a parasitic infection is a learned.

8. How is self-medication knowledge acquired?
Individual foraging behaviors are mainly acquired by learning from social models, first from mother, then from peers, and from individual post-ingestive experiences. In the wild, the kinds of substances monkeys rub on their fur vary from site to site. Even when the same substances are available at several sites, the items a particular group uses for rubbing is likely to be different, suggesting a socially transmitted pattern of use. Leaf swallowing behavior in chimpanzees as a means of physically expelling intestinal parasites appears to have its origins in the opportunistic feeding behavior of some “pioneering” individuals.

The spread of the self-medicative behavior within the group seems to be influenced by social models. Unfortunately, learning from mom and the needs of her offspring’s may be in conflict. Mamber goats teach their kids to avoid intake of tannin-rich P. lentiscus, but P. lentiscus has strong deworming properties. In fact local goat breeders to tether parasitized animals close to P. lentiscus bushes. Therefore, a young parasitized mamber goat must learn on its own – sensing the benefits eating P. lentiscus while parasitized and relying on its own experiences – that is contrary to mother’s teaching.