Original article
Are ethnopharmacological surveys useful for the discovery and development of drugs from medicinal plants?
- Open Access funded by Sociedade Brasileira de Farmacognosia
- Under a Creative Commons license
Abstract
Ethnopharmacological
and ethnobotanical approaches are described in the literature as
efficient to identify plants of interest for phytochemical and
pharmacological studies. In the present work, we reflect on the quality
of the data collected in ethno- directed studies. In accordance to the
problems identified in published studies, and their theoretical and
methodological underpinnings, we believe that these studies are poorly
suited to contribute to the advancement of research aimed at the
development of novel drugs.
Keywords
- Ethnobotany;
- Ethnodirected;
- Ethnomedicine;
- Traditional uses
Introduction
Despite
the richness of the ethnopharmacological surveys performed worldwide,
and the increase in knowledge of the use of natural resources by local
communities (Albuquerque et al., 2012),
particularly in Brazil, many of the collected data were found not to be
sufficiently sound for bioprospecting purposes. In fact, the
ethnopharmacological/ethnobotanical approach has been progressively
losing its appeal as a tool for systematic identification of novel
pharmaceutical drugs because this approach has failed to locate new
species that could represent interesting candidates for further
phytochemical and pharmacological studies (Gertsch, 2009). The reasons for this failure include the poor quality of many studies (Albuquerque and Hanazaki, 2006 and Albuquerque and Hanazaki, 2009)
both from a pharmacological point of view and in the data collection of
ethnopharmacological surveys. From the pharmacological side, many of
the problems are associated with limitations in the methods employed and
misinterpretations of the bioassay results (Houghton et al., 2007 and Gertsch, 2009). Nevertheless, in order to characterize the scenario we have to consider the affirmation of Gertsch (2009), which states that:
“(…)
in the last 20 years few significant discoveries have been made. This
may in part be based on the fact that the many of most relevant plant
constituents, including the psychoactive, poisonous, and antitumor
natural products, have already been found and we have to work harder to
find yet another molecule that will change the world”.
In
ethnopharmacological surveys, the problems include inadequate design
for data collection, and the misinterpretation of the role medicinal
plants play in the medical systems of local and indigenous communities (Etkin, 1993, Moerman, 2007, Albuquerque and Hanazaki, 2006 and Albuquerque and Hanazaki, 2009).
For instance, our current database relative to the local uses of the
Brazilian medicinal flora is quite large, but it exhibits various
methodological biases that limit our power of interpretation, as shown
by Medeiros et al., 2013a and Medeiros et al., 2013b).
Furthermore, other authors have mentioned the fragility of taxonomic
information for the species studied in ethnopharmacological studies (Bennett and Balick, 2014 and Rivera et al., 2014).
Considering the problems mentioned, the present manuscript focuses on
issues associated with ethnobotanical/ethnopharmacological data
collection of medicinal plants, a topic that has been neglected in the
ethnopharmacological literature (Etkin, 1993; Reyes- García, 2010).
One
should bear in mind that not all records resulting from
ethnopharmacological surveys of medicinal plants can be validated from
the medical point of view for several reasons: 1. Data collection does
not take into consideration the full scope of the particularities of the
local medical systems; 2. Records include a maladaptive culture trait (i.e.,
therapeutic indications that do not seem to be biologically effective);
and 3. Records include traits exclusively adapted to the studied
population. Therefore, to promote a debate on the
ethnopharmacological/ethnobotanical approach with respect to
bioprospecting, henceforth designated as ethnodirected, the present
article discusses the main weak points of this approach and possible
alternatives to overcome its limitations, based on experiences from our
research group. The topics discussed here include sampling issues, the
selection of plants relevant for bioprospecting based on their
popularity and versatility, and the omission of information
indispensable for efficiently testing the plants.
In
this manuscript we are do not consider that bioprospecting and
ethnopharmacology have the same meaning, but rather we are critically
reflecting on the direction commonly adopted by ethnopharmacological
studies that seek to increase knowledge for the discovery of new drugs
from natural products. The following considerations aim to lead to a
reflection on the tools that are currently used by researchers who
explicitly aim to collaborate on the above-mentioned issues.
Efficiency of the ethnodirected approach
With
respect to the search for new drugs, some studies have compared
ethnodirected to other approaches, the random approach in particular,
which consists of randomly collecting plants for phytochemical and
pharmacological screening (Balick and Cox, 1996, Khafagi and Dewedar, 2000, Oliveira et al., 2011 and Slish et al., 1999; see also Cragg and Newman, 2003;
2005). In several instances the results of ethnodirected investigation
are best compared to a random search for plants for specific therapeutic
purposes. Khafagi and Dewedar (2000)
investigated plants with antimicrobial activity that grow spontaneously
in Sinai (Egypt) and found that 83% of the plants selected using the
ethnodirected approach elicited such properties, while only 42% of the
randomly selected plants did. Similarly, Slish et al. (1999)
found that four out of 31 plants selected in Belize using the
ethnobotanical approach exhibited vascular smooth muscle relaxant
activity, while none among the 32 randomly collected ones exhibited this
property.
However, the
interpretation of the results might lead to divergent conclusions on the
efficiency of the ethnodirected approach as an indicator of promising
plants. For instance, Khafagi and Dewedar (2000)
found that the random approach led to the identification of a larger
percentage of species with strong antimicrobial activity (13.9% versus
8.3%) even though the ethnobotanical approach allowed for the
identification of a larger number of plants with antimicrobial activity.
Thus, one of the lessons we could draw from this example is that, in
some cases, finding a small number of plants that exhibit a property of
interest to a high degree might be more relevant than finding a larger
number of plants with lower levels of activity. Therefore, even in cases
in which the ethnopharmacological approach seems to stand out, our
enthusiasm might lead us to reach unsound conclusions regarding its
actual relevance for the search of new drugs. Case et al. (2006)
reported on the limitations of the ethnopharmacological approach in
their study on drugs used for the treatment of respiratory diseases in
Manus province, New Guinea. These authors selected the informant
consensus model to identify the plants with potential pharmacological
activity, but found that their underlying assumptions were inadequate to
predict antimycobacterial activity. Hence, they warn that ethnodirected
approaches should be considered limited while wider-scoped studies are
needed to elucidate their relevance or incompatibility.
Although
the results from an ethnodirected approach will overlap with those of a
random approach, studies indicate that there is no full agreement
between the two methods in some cases. Examples can be found in the
search for novel anticancer agents. Spjut (2005)
reported that active species were detected more frequently (1.4- to
2.6-fold greater rate) from the group of medicinal and poisonous plants
in relation to a plant species screened at random. Gyllenhaal et al. (2012)
found that for many cancer cell lines, the random approach returned
better results than the ethnomedical selection approach; as occurred
with MCF-7 (human breast cancer) for which the random approach success
rate was higher than the ethnomedical. The authors relativize their
findings by arguing that the results could be due to the much higher
sampling for random collections. However, according to the authors:
“The
overall analysis suggests that plants collected based on ethnomedical
use may in fact have a somewhat higher rate of positive bioassays on a
per-species or per sample basis, although a portion of these assay
results may be due to ubiquitous bioactive compounds. Ethnomedical
collections in general may nevertheless play a useful role in drug
discovery programs due to this elevated rate of bioactivity”.
In the last two decades, few significant discoveries have been made in the field of ethnopharmacology (Gertsch, 2009).
Some candidate compounds identified by the bioprospecting
research-based ethnomedical approach, as developed by Shaman
Pharmaceuticals, have failed, which leads to the suggestion that an
ethnodirected approach is not feasible for the development of novel
drugs (Clapp and Crook, 2002).
By contrast, the random approach has made effective contributions to
the development of drugs, many of which are still available for the
treatment of various diseases. One example is the search for new
anticancer drugs conducted by the National Cancer Institute (NCI) of the
United States. They employed the random approach in a program developed
in the 1960s, resulting in several agents of clinical relevance such as
“taxanes and camptothecins, but their development into clinically
active agents spanned a period of some 30 years, from the early 1960s to
the 1990s” ( Cragg and Newman, 2005). Between 1960 and 1982 the NCI investigated about 35,000 plants before the program was suspended ( Beutler et al., 2012). According to Cragg and Newman (2005):
“This
plant collection program was terminated in 1982, but the development of
new screening technologies led to the revival of collections of plants
and other organisms in 1986, with a focus on the tropical and
sub-tropical regions of the world”.
The
examples described above raise a question: why do scientists still
assert so strongly the benefits of the ethnodirected approach versus the
random one when its application in practice does not lead to
significant advances in the development of particular drugs? Why do they
keep on conducting studies aimed at making lists of species and
therapeutic indications? We cannot give definite answers to these
questions but we hypothesize that the ethnodirected approach is perhaps
only useful for particular types of diseases. Only well-conducted and
rigorous ethnopharmacological/ ethnobotanical studies might clarify
these issues.
