Why might someone develop resistance to a pharmaceutical drug based on one active plant ingredient but be successfully treated by the plant itself? Renowned ethnobotanist Mark Plotkin argues that modern science commits a persistent error as it seeks to isolate one component of a plant without considering the rest. Similarly, physician-scientist Karyemaitre Aliffe argues that just as conditions in a vineyard affect the quality of the grapes, growing therapeutic plants in a lab can alter their desired effects. In the below excerpt from a Bioneers panel discussion, Plotkin and Aliffe discuss what we miss when we oversimplify nature’s complexity, and how we can correct our thinking. 

Plotkin is a renowned ethnobotanist and award-winning eco-activist, co-founder of the Amazon Conservation Team, and best-selling author of “Tales of a Shaman’s Apprentice and Medicine Quest: In Search of Nature’s Healing Secrets.” Aliffe is a physician-scientist and leading expert on the healing properties of cannabis. He has taught at Harvard and Stanford universities and has 35+ years of experience in natural products research, including explorations in many remote global regions. 

Note: The below excerpts are from a larger discussion that took place during a virtual panel at a Bioneers online conference in 2021, Human-Visionary Plant Relationships in the Anthropocene. They have been edited for clarity.

MARK PLOTKIN: An important point I want to make is that, in general, there’s a big difference between taking a whole plant with all the complex compounds it contains and taking a pharmaceutical drug based on just one supposedly “active” ingredient found in a plant. Take quinine (Cinchona officinalis): that tree, native to the Andes, has probably saved more lives than any other tropical species because it’s long been the most effective treatment for malaria. The modern Western scientific approach has been to isolate one of the alkaloids found in the plant and make pharmaceutical anti-malarial drugs based on it, but the massive use of that sort of single alkaloid has resulted in the malaria-causing plasmodium parasite beginning to develop resistance to it. I have a physician friend in Colombia who tells me he is able to treat even quinine-resistant malaria by using the whole bark from the tree instead of the pills because the bark contains 15 different compounds and the parasite has a much harder time developing resistance to it. 

The modern scientific reductionist approach repeats the same sorts of mistakes over and over, and it’s one reason we’re facing more and more drug-resistant diseases. Useful in treating malaria is another plant, artemisia. Yet the pharmaceutical industry is repeating the same pattern as with quinine, and once again we’re sure to generate artemisia-resistant malaria. I’m not saying we should never develop synthetic drugs based on compounds found in plants, but we have to do it carefully. And we need to have far more understanding of and respect for nature’s complexity, because honestly our supposedly scientific, high-tech methods often fail or create unintended consequences because they are far too simplistic in their approach to very complex, interdependent living systems.

Time and time again, we look at nature and want to snatch and grab one gene, one bacterium, one alkaloid and bring it back to the lab and make a useful, uniform product that we can mass produce and make money from, but it’s just not that simple. That’s not how nature operates. And most of the time we don’t listen to the people who know the most about how nature operates and what it can teach us, and that’s the Indigenous people in the most biodiverse places on the planet.

An example is the fungus Cordyceps. My colleague Glenn Shepard was long interested in a plant called piripiri, a chemically inert sedge related to grass that tribes in the western Amazon have long told us is an effective female contraceptive and also has other properties. When researchers tested it in the lab, they couldn’t find any chemical activity at all, but Glenn Shepard, who speaks Machiguenga and has worked with that tribe for decades was talking to one of the Machiguenga shamans about this and the shaman gave him the plant to take. Soon thereafter, Glenn felt great and began juggling masterfully, something he had never been able to do well previously. He began studying the plant in a bit more detail and found that the secret of the sedge isn’t the plant itself but a species of cordyceps fungus which contained seven new-to-science alkaloids. Again, scientists looking for the single ingredient missed the complex fungal-plant relationship.

Now I’m not arguing against the creation and use of modern, synthetic drugs based on natural molecules. After all, the great chemist Albert Hoffman created LSD-25 based on compounds from the ergot fungus, but there are so many millions being invested in these industries now that very little attention is being paid to protecting the original habitats of these plants. And climate change is threatening or causing the extinction of some species, including psychoactive ones. It will be very hard to preserve many of these species without tackling climate change.

My worry is that at the same time that we have more and more access to these substances, the roots, both botanical and cultural, are dying. That’s why the Amazon Conservation Team and other groups…are so focused on defending cultural and biological diversity, so we don’t wind up with a world with no primary forests, in which the only wildlife are cockroaches and pigeons, and all the shamans have passed on without being able to pass on their knowledge and their languages. It’s a conundrum: We have more information and greater access to plants and plant lore than ever before, but we’re also destroying the habitats of those plants at a faster and faster clip. We’re burning the candle at both ends…and we will need curanderas/curanderos and microchips to build the medicine of the future, which I think will be some sweet spot somewhere between those two approaches. And we still need to develop the patience to listen with respect and patience to the ones who know best what nature has to offer us, the Indigenous shamans and healers, if we don’t want to miss the opportunity to discover new (to us) antivirals, antimalarials, entheogens, etc., all of which we are most likely to desperately need in the years ahead. There’s a lot more out there. The rainforest has answers to questions we have not yet asked!

DR. KARYEMAITRE ALIFFE: …Another interesting concept worth looking at because it reveals some other limitations of current scientific approaches is the “entourage effect.” In the domain of pharmaceutical development, researchers are always studying one single agent at a time, the “silver bullet” approach. They are not taking in all the complex interactions occurring in the human, physiologic and cellular environments. They just want to observe effects induced by a specific single molecule, but the drugs they develop will ultimately be given to real human beings who are, especially if they’re older, most likely already taking a wide range of other prescription drugs for conditions such as high blood pressure, diabetes, high cholesterol, mood disorders, etc. Most people are functionally engaged in polypharmacy. They’re taking more than one drug, and those drugs have not been studied thoroughly in combination. Is there an entourage effect? Are there complementary activities or even untoward effects from that combination? That’s rarely studied or even considered.

And, of course, when you add in cannabis, large swaths of the medical establishment holding prejudices against it complain that cannabis may interfere with their prescription drugs, as though their prescription drugs were invariably providing a more important therapeutic action than cannabis, and as though some of the drugs they prescribe don’t have potentially dangerous side-effects. Drugs such as Ambien are far more likely to cause people to do all kinds of wildly unpredictable things, while sleepwalking, or even sleep-driving on the freeway, than any amount of cannabis.

Bear in mind that cannabinoids are just enhanced salicylic acid derivatives, the same family of molecules as aspirin. They’re not nearly as esoteric as many current psychotropic pharmaceuticals.

One last thing I’d like to delve into is the relationship of climate change and of environmental contexts on the therapeutic potential of cannabis. The cannabinoids within cannabis that we explore for their therapeutic potentials are “secondary metabolites” — molecules that are not directly involved in the growth, reproduction and proliferation of a plant, but that provide selective advantages over other plants, microbes or even animals that may diminish that plant species’ ability to thrive and proliferate. Secondary metabolite profiles change as plants respond to environmental change. In the case of cannabis plants, such compounds include cannabinoids, terpenes, and cannaflavins, a class of flavonoid metabolites with enormous anti-inflammatory potential (discovered by one of our esteemed colleagues, Dr. Marilyn Barrett, who worked with us at Shaman Pharmaceuticals). 

So, when you’re looking at therapeutic compounds in cannabis plants, you have to look beyond just the simple genetics of a particular cannabis strain. You have to study the secondary metabolites — just as in viticulture, where grape quality depends on what the French call the “terroir,” the very specific circumstances and conditions of the soil, rainfall, temperatures and the general environment. Plants are super sensitive to their local conditions. Some studies have even shown that if you introduce certain insects intentionally into your cannabis grow, it can induce increased production of particular secondary metabolites.

This has major implications. For example, if you seek to grow cannabis in a highly controlled, clean and sterile environment, it may not necessarily be to your advantage in terms of producing the types of therapeutic compounds you want. When consumed by humans, cannabinoids interact with our endocannabinoid system; and our own endocannabinoids (endogenous cannabinoids) are derivatives of arachidonic acid, a common molecule in human and plant physiology that is involved in stress responses. To simplify a bit, the point is that there is continuity between plant and animal (and therefore human) physiology. When plants are stressed, they produce molecules to help manage those stressors, and these molecules can often help humans manage stress. So, if you’re raising pampered, unstressed plants, you may not produce the therapeutic compounds you are seeking. This is another example of the need to look at whole complex systems and where the plant and the work you’re trying to do fit into the larger world, where everything is interconnected.