Transitioning to 21st Century Medicine: The Promise of Whole Plant Medicine

Medical Care: The Big Picture

Suppose some medical problem arises and you go to a doctor to have your problem treated. To be able to perfectly treat any problem you might have, your doctor would have to have a complete understanding of:

1. How your body works. Your doctor would have to have a perfect understanding of the science behind human health, including, for example, human anatomy, physiology, cell biology, neurology, and psychology. He would have to have perfect understandings both of the body functioning that’s common across people in society (population health), as well as that which is idiosyncratic to you (genomics).

2. How disease works. Your doctor would have to have a perfect understanding of the science behind the symptoms, causes, and nature of progression of all human disease, including, for example epidemiology and pathology.

3. How medications and treatments address disease. Your doctor would have to have a perfect understanding of disease treatment, including, for example, pharmacology, physical therapy, and surgery.

Of course, no doctor out there has such a complete understanding of human health and disease. In fact, all doctors on the planet taken as a whole do not have such a complete understanding of health and disease.

Society’s ability to treat medical conditions is intimately tied to the extent of its knowledge and use of science and technology. No doubt, we’ve come a long way over the millennia. On the other hand, we still have so far to go.

Origins of Modern Drug Discovery

Focus, now, specifically on medications used to treat dysfunction and disease (as opposed to devices, surgery, diet, etc.).

Isolation of Plant Compounds

Before the 19th century, medicines generally consisted of plants and plant-based extracts, which contain a large variety of bioactive compounds. Advances in natural product chemistry and extraction technologies during the 19th century stimulated a “seminal” transition in Western medicine, shifting the focus away from multi-component extracts (whole plant), toward purified isolates, either natural, or later, synthetic (see Figure 1).

Figure 1

The isolation of morphine from opium by Friedrich Sertürner in 1805 was “the first isolation of a natural product from a plant,” which “kick-started natural product chemistry.” As researcher Eyan Huxtable notes (1):

"The isolation of morphine from opium —the first isolation of a natural product—was a seminal event in the development of pharmacology as an independent discipline. The purification kick-started natural product chemistry and quickly led to the isolation of a host of other alkaloids [including strychnine, caffeine, quinine, nicotine, and codeine].…

As a consequence of his studies, Sertürner established the principle that plants contain active substances that, on isolation, carry the therapeutic properties of the plant."

Over subsequent decades, analytical chemists and apothecaries (medicinal chemists) continued to isolate and characterize “the active principles in medicinal plants.” By the latter half of the 19th century, pharmacology had been established as a scientific discipline (2). Furthermore, the isolation and purification of plants’ active compounds became increasingly essential for medications for several reasons, including the newfound ability to administer accurate doses, the ability to prevent toxic effects due to impurities in the plant, and, by the end of the century, the ability to synthesize structurally similar substances based on better understandings of chemical structures (3).

Anti-Bacterials: Research and Discovery

During this period, the latter half of the 19th century, the top ten causes of death were all due to bacterial infections. Bacteria, such as those causing tuberculosis, diphtheria, scarlet fever, and whooping cough, spread through the air from person-to-person. Bacteria, such as that causing malaria, spread from insects or animals to people. Bacteria, such as that causing dysentery, cholera, or typhoid fever, spread due to lack of proper sanitation. Finally, bacteria causing post-injury infections spread due to lack of proper medical sanitation practices (see Figure 2 below).

Paul Ehrlich, a late-19th century German researcher, significantly shaped the course of drug discovery in Western medicine. Ehrlich studied how our immune systems respond to bacterial infections, that is, how our bodies generate antitoxins, or antibodies, to fight the toxins released by bacteria that have invaded our systems. Ehrlich’s research led to the magic bullet concept: the idea that an isolated compound (the treatment) could be used to hit a single disease target in the body (bacterial infection), thereby curing the disease, while leaving the rest of the body intact. Magic bullets are clean drugs: they have single actions with few side effects (4). Ehrlich’s 1909 discovery of Salvarsan, “the first effective – but rather toxic – remedy for syphilis,” was the first magic bullet discovered (penicillin was another) (5). In 1908, Ehrlich received the Nobel Prize in Physiology or Medicine for his research on our immune response to toxins (6). He also pioneered the concept of cell receptors, ligands, and the lock-and-key concept of drug target mechanisms (7). That is, he provided the notion of a clear entity (a receptor) for medications to target.

One Drug, One Target Paradigm

Ehrlich’s work has had a profound effect on drug discovery since then, for establishing the magic bullet as the gold standard – the one drug, one target paradigm – for drug discovery (8):

"Currently, the main paradigm in drug discovery is the development of target-specific inhibitors... This mainstream view has its origins in the so-called “magic bullet” as enunciated by Paul Ehrlich over 150 years ago. Indeed, such concept was engraved in the mind of many health professionals and researchers as the top achievement in drug discovery."

In short, subsequent drug discovery efforts focused on matching isolated substances (one drug) to isolated targets. Researchers searched for isolated compounds (as opposed to whole plant extracts) from natural products — or better yet, they artificially synthesized compounds to serve as treatments. And they used those isolated compounds to act as activators (ligands) of isolated targets, such as specific enzymes or cloned receptors (as opposed to more holistic tissue cultures). This new paradigm was strictly adhered to by Western medicine. The Western medicine perspective starkly contrasted with the approach taken by Eastern medicine, namely, using whole plant medicines to address holistic health problems (see Figure 2).

Figure 2

Continued research efforts led to advances in pharmacological science and technology. Efforts to focus on single or isolated treatments were aided by advances in (i) extraction technologies (mass spectrometry) enabling researchers to better isolate compounds from natural ingredients; (ii) chemical science enabling researchers to understand and recreate the structures of extracts; and (iii) synthesis technologies that enabled researchers to artificially recreate and potentially enhance natural products (9)

Efforts to focus on single or isolated targets were aided by advances in in vitro tissue cell culturing (10). Efforts to match isolated treatments to isolated targets were aided by advances in bioinformatics (such as genomics, metabolomics, proteomics) and screening (for example, HTS, microarrays, assays, chemical libraries) technologies (11).

Bifurcation of Holistic and Western Medicine

The development of the science and technology needed for researchers to be able to identify and isolate single compounds from plant extracts changed the course of Western medicine. This ability led scientists to the principle that a single active component in a plant acting on a single target in the human body was wholly responsible for the plant’s therapeutic effects. And it was this principle that caused the practice of medicine to bifurcate into two forms: conventional and alternative.

Centering around the use of purified isolates in treating disease, conventional medicine, also known as Western or allopathic medicine, is reductionistic in nature. Its paradigm is “one drug, one target and one disease" (12). In contrast, traditional alternative and complementary forms of medicine, which include, among others, herbal or whole plant medicine, traditional Chinese medicine, and Ayurvedic (Indian) medicine, are more holistic in nature. Alternative forms of medicine view plants and people each as embodying intertwined systems of activity. This alternative paradigm views diseases as being due to systemic problems in the body and draws upon synergistic relationships in whole plant extracts to treat multifaceted dysfunction in the body (13).

The newfound ability to isolate individual compounds, together with the one-compound-one-target presumption, radically changed how plants were used in Western medicine. Henceforth the modern healthcare industry insisted on the exclusive use of isolated compounds in healthcare – rather than whole plant extracts – for three reasons (14). The use of isolates enabled:

1. Accurate dosing of medications,

2. Elimination of toxic effects due to impurities in plant product, and

3. Synthesis of related compounds for use in other valuable drugs.

It is crucial to understand that in Western medicine, drug purity is directly linked with quality (15). This demand for purity comes from the assumption that the compound forming the basis of the drug is the sole factor causing the desired outcome. In this case, the presence of any impurities – intentional (dilutors or toxins) or unintentional (residual plant compounds) in nature – might influence the efficacy (potency) and/or safety of the pharmaceutical products (16). This assumption, which forms the basis of Western medicine, stands in stark contrast to the fundamental assumption held by practitioners of whole plant medicine that multiple compounds within plants work together in our bodies to create synergistic therapeutic outcomes (17).

The Current State of Pharmacological Science and Technology

Sertürner’s isolation of morphine kicked off 19th century through early-20th century advances in microbial and pharmacological science and technology. Numerous other discoveries occurred in compound extraction, purification, and synthesis, not to mention Ehrlich’s work in establishing the one drug-one target paradigm. Taken collectively, these myriad advances paved the way for the introduction of a series of vaccines, together with improvements in sanitation, that largely eradicated death due to acute disease (see Figure 3).

Now that acute infections were treatable, mid- and late-20th century people were able to live longer lives. The bad news is that since treatments have since been available for acute infections, people have been living long enough to suffer and die from chronic health conditions (see Figure 3).

Figure 3

The ability to treat acute infections was, indeed, a tremendous achievement of the 19th and 20th century pharmaceutical industry. At the same time, however, during this period, Western society became locked into a specific drug discovery paradigm: one drug, one target. This paradigm was designed to address a specific disease environment (single-faceted bacterial infections), which has since been replaced by a completely different environment (multi-faceted chronic conditions). Yes, acute infections still occur, but we now have the treatments to address them (18).

Yet, since we’ve conquered acute diseases, what we’ve needed – and still lack – are treatments that effectively address the new, multi-faceted diseases that have come to replace acute diseases as the main causes of death.

Over recent decades, pharmaceutical companies have been increasing their resource expenditures on new drug discovery. While science and technology have progressed enormously, the discovery of new drugs that have been effective in treating our current health problems has been dwindling. As Rutgers researchers report in, “Plants and human health in the twenty-first century” (19):

"… [D]espite the remarkable progress made by chemistry, pharmacology, molecular biology, genome research and high-throughput screening, the NCE [new chemical entity] pipelines of pharmaceutical companies are at historically low levels."

At the same time, historical methods used to treat disease are becoming less effective, for two primary reasons. First, new bacteria and other pathogens have been emerging that are resistant to traditional treatments. Second, existing medications designed under the one drug, one target paradigm are not effective at addressing chronic conditions with multifaceted targets. More from the Rutgers researchers (20):

"The NCE paradigm of the twentieth century attempts to treat complex diseases with a ‘single golden molecular bullet’. The first flaw in this paradigm appeared relatively recently when problems of resistance to antimicrobial and anticancer drugs became apparent. The multifactorial nature of many complex diseases, such as diabetes, heart disease, cancer and psychiatric disorders, is also an important consideration. Most of these diseases cannot be ascribed to a single genetic or environmental change but arise from a combination of genetic, environmental or behavioral factors."

The healthcare industry has been using an old paradigm to address healthcare for a new world. What the industry needs is a new paradigm that will address conditions present in the new environment.

Holistic Medicine

New-Found Acceptance

Parts of society have already been moving in a new direction. Patients, for their part, have been transitioning away from the take-a-pill-to-treat-a-symptom approach to a new holistic, live-a-healthier-lifestyle approach. What used to be considered alternative lifestyles – traditional Eastern practices, including functional foods, whole plant medicine, and meditation – are becoming more mainstream. As a case in point, a 2018 press release by Hexa Research reveals large expected growth in the global herbal medicine market, “driven by rising popularity of herbal therapeutics compared to conventional drugs” (21):

"The global herbal medicine market is expected to reach USD 117.02 billion by 2024, driven by rising popularity of herbal therapeutics compared to conventional drugs. The market for herbal medicines and remedies is anticipated to record profitable growth due to their cost-effectiveness as compared to allopathic ones."

The Federal government is also dipping its toe into the herbal water. In 1994, Congressed passed the Dietary Supplement and Health Education Act (DSHEA). Under this new act, dietary supplements, which include herbs and botanicals, can be more freely marketed, as long as no claims are made as to disease prevention, curing or detection. Instead, manufactures can make structure–function claims about products related to improving or maintaining normal physiological functions of the body (22). According to the FDA, “In the 25 years since the Dietary Supplement Health and Education Act of 1994 (DSHEA) was enacted, the dietary supplement market in the U.S. has grown from approximately 4,000 products to somewhere between 50,000 and 80,000 products” (23).

At the same time, healthcare providers, while not exactly embracing whole plant extracts, have at least realized the benefits of more holistic treatments. Providers are increasingly prescribing drug cocktails, or combination therapy, that is, combinations of single isolate pharmaceutical compounds, to treat diseases that have become resistant to single-therapy treatments or that have never been effectively addressed by single-therapy treatments. Combination therapy has been used to treat, for example, tuberculosis, HIV/AIDs, cancer, cardiovascular disease, metabolic disease, and autoimmune disease (24–27).

Mechanisms of Action

Advocates of more holistic approaches to medicine generally tout the synergisms associated with whole plant extracts. Essentially, whole plant synergies result from having a multiplicity of compounds that are simultaneously absorbed by the body and work on different targets to create complementary effects. As Brazilian researchers Fabio Carmona and Ana Maria Soares Pereira so pithily express (28):

"The mechanisms of synergism among the compounds present in a single herbal extract are mainly related to two factors: the simultaneous solubility of a group of substances with different polarities, and the multiplicity of targets that these substances can act on, including enzymes, receptors, ion channels, transport proteins, antibodies, and many others."

As compared with using purified isolates, the use of whole plant extracts may provide better outcomes at lower doses with fewer side effects (29).

Future Potential

More holistic approaches to medicine, including whole plant medicine, have tremendous potential to help our healthcare system better address the 21st century environment for a variety of reasons.

Nature’s Biodiversity

Newer technologies being developed to enhance drug discovery efforts increasingly draw upon synthetic compounds as potential treatments for disease. Synthetic compounds are structurally simpler than natural molecules, which makes them easier to characterize and analyze. This brings to mind the idea of looking for your lost car keys underneath the street lamp, because that’s where the light is. It is thus not terribly surprising that recent drug discovery efforts using synthetic compounds as potential treatments have not been fruitful. On the other hand, nature offers a virtually untapped resource for researchers, which contains vast numbers of structurally complex compounds that have been naturally designed — “co-evolved” — to work together. More from Rutgers researchers (30):

"Nevertheless, comparative analysis of structural diversity in natural-product mixtures and combinatorial libraries suggests that nature still has an edge over synthetic chemistry, despite the fact that combinatorial libraries display more elemental diversity. Indeed, superior elemental diversity does not compensate for the overall molecular complexity, scaffold variety, stereochemical richness, ring-system diversity and carbohydrate constituents of natural-product libraries. It is generally believed that the complexity, diversity and vast number of plant-produced secondary metabolites will continue to constitute a resource beyond the capacity of current synthetic chemistry."

Omics and Bioinformatics Technologies

The completion of the Human Genome Project in 2003 (31) opened the research floodgates, leading to a better understanding of how our bodies work, specifically, the nature of similarities and differences across individuals and populations. The Project led to vast new areas of study, including (32):

• Genomics: the study of the structure, function, evolution, and mapping of the genome.
• Transcriptomics: the study of how genes express themselves.
• Proteomics: the study of proteins, that is, molecules that perform a host of functions in living organisms, including catalyzing metabolic reactions and responding to stimuli.
• Metabolomics (plant and human): the study if metabolites, that is, the substances involved in cell metabolism.

Research into all the different omics has created a huge glut of information, which, in turn, has led to the development of a whole new set of tools to analyze these data, bioinformatics.

• Bioinformatics: “an interdisciplinary field that develops methods and software tools for understanding biological data, in particular when the data sets are large and complex.”

Notably, the omics technologies, together with bioinformatics platforms, are much better suited to the study of whole plant diversity and synergy than any other technologies to date. In other words, these new technologies open the door to the study of whole plant medicine (33).

Systems Biology

Integration of the new life sciences with technologies are shifting the way researchers approach living organisms, from a reductionist view to a systems view. With a deeper understanding of how our bodies work, together with the tools needed to continue exploring new-found complex interrelationships, researchers are gaining new integrated understandings of living cells and organisms. Researchers are now redirecting their energy away from focusing on treating symptoms to focusing more on treating underlying disease.

Unsurprisingly, within this new systems paradigm there’s been an increasing acceptance of whole plant medicine, which "has been described as the ‘‘herbal shotgun’’ approach, as opposed to the ‘‘silver bullet’’ method of conventional medicine to distinguish the multitargeted approach of herbals from the monotarget approach of synthetic drugs addressing specific enzymes or receptors.…In recent years this ‘‘shotgun approach’’, understood as a therapeutic strategy which aims at multiple targets in an organism, has gained an increasing acceptance" (34).

Transitioning to 21st Century Drug Discovery

One of the primary reasons researchers have historically focused their studies on using isolated compounds to act on isolated targets is that doing so makes an intractable problem as easy as possible to manage. Unfortunately, simplifying the problem to make it easier to find solutions has led to solutions that don’t solve the problem. So then the task with which researchers are now faced is one of trying to address the more difficult problem of finding complex substances (e.g., combination therapies such as whole plant extracts) that address dysfunction in complex systems (people with chronic health conditions).

The good news is twofold. First, more systemic approaches to medicine – whole plant medicine in particular – have existed for thousands of years. A rich store of knowledge gathered over the millennia, for example embodied in traditional Chinese and Ayurvedic medicine, exists to guide practitioners in developing and applying combination therapy and whole plant medicine (ethnopharmacology).

Second, the science and technology of drug discovery has come a long way since Sertürner successfully isolated morphine from poppies. More than two centuries of improvements in chemistry and extraction technologies and almost three decades of improvements in omics sciences and bioinformatics technologies has better prepared researchers to shift to a new paradigm.

What’s needed is to combine the best of Eastern and Western science and technology to discover the complex substances needed to treat our modern complex conditions.

The Challenge

Working with complex systems is difficult because they have funky characteristics, such as emergence, that is, synergies, where 1 + 1 = 3, and non-linearities, where small changes in initial conditions can cause large differences in outcomes. Perhaps an example will help clarify the challenge.

Researchers at St. Jude Children’s Research Hospital in Memphis, TN, conducted a study using two different treatments for leukemia, mercaptopurine (MP) and methotrexate (MTX).35 The researchers tested four different treatment scenarios:

i. MP: MP alone

ii. H-MTX: A high dose of MTX (H-MTX) alone

iii. MP + L-MTX: MP in combination with a low dose of MTX (L-MTX)

iv. MP + H-MTX: MP in combination with a high dose of MTX (H-MTX)

The researchers reported, “Based on changes in gene expression, we identified 124 genes that accurately discriminated among the four treatments.” What the study showed is that the isolated treatments, MP alone and H-MTX alone, generated much more activity than the combination treatments, MP + MTX, did. Specifically, the researchers reported that “Only 14% of genes that changed when these medications were given as single agents also changed when they were given together.” If I’m understanding this correctly, when MP and MTX were administered separately, a total of 124 different genes reacted. However, when the two treatments were combined and administered together, only 17 of the original 124 genes still reacted under the new scenario. In this case, then, a lot of activity was prevented (perhaps unwanted side effects) by combining the treatments, rather than by administering either of them separately.

What we have, then, is an inability for researchers to predict what will happen when separate treatments are combined, simply by knowing what will happen when the treatments are undertaken in isolation. In this case, researchers must now investigate not just single components in isolation, but all different combinations of the individual components. The number of tests researchers must conduct under this new paradigm is thus exponentially greater than the number needed under the old, one drug, one target paradigm. That’s the challenge.

What’s Needed

The current environment in Western medicine is not amenable to implementing a new system that combines traditional Eastern and Western approaches, that is, the paradigm needed to address 21st healthcare problems. Many of the forces in the current Western system – much science and technology, the FDA approval process, provider methods of practice, payment systems, etc. – are geared toward supporting a one drug, one target paradigm. As such, several aspects of the current system must change to make the environment more receptive to the new paradigm. Specifically, Western society needs: a new mindset for participants in the healthcare system; new technologies compatible with combination therapies; standardization of supply of whole plant products; and new regulations supporting development, safety, and efficacy of combination therapies.

A New Mindset

As mentioned earlier, the new omics and bioinformatics sciences and technologies have led to whole new understandings of systems biology. Unfortunately, the majority of the Western medicine community has long-since been entrenched in the old, one drug, one target environment. Consequently, the industry must change its training and practice perspectives, from those centered around isolated bioactive agents and generic targets, to those that are more consistent with holistic conceptions of living organisms, one which recognizes both the homogeneous, as well as the heterogeneous, nature of patients (36).

New Technologies

The completion of the Human Genome Project marked a transition point in time regarding the process used to discover new drug candidates (37). Before the genome was sequenced, the new drug discovered efforts involved the forward pharmacology approach. Researchers would start by finding new drug candidates. These were discovered by identifying active ingredients identified either from traditional use of medicinal products, from libraries of molecules whose pharmacology had been determined, or simply by chance. Once a drug candidate was found, researchers tried to find a target in the body that the drug could be used to affect.

The Human Genome Project provided a much better understanding of how substances act on various targets in the body to create outcomes. This new understanding changed the nature of drug discovery to the reverse pharmacological approach. Researchers now start by finding a target in the body to hit so as to change an outcome, from an “unhealthy” one, to a “healthier” one. After finding the target, new technologies are used, high-throughput screening (HTS) technologies, which enable researchers to screen very large volumes of different substances.

Whole plant extracts contain hundreds of different compounds, many in trace amounts, which makes them exceedingly difficult to work with. Consequently, HST technologies have evolved to employ synthetic compounds, which are easier to characterize and analyze. Suppliers have been focusing on creating libraries of that contain vast arrays of isolated and well-characterized synthetic compounds. Unfortunately, whole plant extracts are now incompatible with many current HST technologies. What’s needed, then, is more advanced science and technology enabling researchers to more quickly and easily extract, characterize, and analyze compounds from natural sources (38).

The good news is that science and technology are both moving in this direction. For example, researchers are developing a new branch of pharmacology, network pharmacology, which combines systems biology with polypharmacology in the development of combination therapies (39). Furthermore, new characterization and screening technologies, combined with “spectral databases” are emerging as tools for discovering potential natural product therapies (40). Finally, research in the cannabis industry in particular is generating new extraction (41) and characterization technologies (42) specific to cannabis, but which methods can surely be adapted to use for other whole plant substances.

Standardization of Supply

Perhaps the biggest complaint about whole plant medicine from the traditional Western medicine community is the lack of standardization of whole plant products. The profile of compounds contained in a given whole plant extract and that end up in a patient’s body may vary depending on (i) the plant’s genetics; (ii) the environment in which the plant was cultivated, including the nature of lighting, watering/humidity, nutrition, and stressors (insects, mold, bacteria, etc.); (iii) the methods used to harvest and cure the plant; (iv) the methods used to extract compounds from the plant; (v) the methods used to formulate medications from the plant extracts; (vi) the methods of storing the plant products as they pass through the value chain; (vii) the methods used to ingest the plant products; and (viii) set and setting in which the patient ingests the plant products.

In glaring contrast, Western medicine employs methods and practices to standardize medications all the way through the method of patient ingestion. (How medications react based on individual patients’ sets and settings may still vary.) Every pill a patient ingests is identical from one to the next (within allowable product variances) (43), whereas each sample of whole plant product may vary nontrivially from one sample to the next.

From the perspectives of patients, providers, and payers, the lack of standardization in whole plant medicine creates two overwhelming barriers to adoption: whole plant medicine is incompatible with patients’, providers’, and payers’ needs for medication to be (i) standardized from one dose to the next and (ii) consistently available to patients each time they seek to purchase it. Whole plant medicine simply will not be a viable consideration unless or until both of these barriers have been adequately addressed, if not wholly overcome (44).

I believe the needs of a significant portion of patients will be adequately addressed with industry attainment of the following milestones:

• Manufacturers must adhere to strict testing methods and protocols that ensure the safety of accuracy of labeled medicines.
• Manufacturers must provide full transparency regarding the profiles of ingredients contained in each medication.
• Researchers and providers must better understand how small variances in both (i) the profiles of ingredients contained in medications, as well as (ii) the patients’ biology (determined by a combination of genetics, lifestyle, and environment) affect therapeutic outcomes. It may be the case that patients can withstand relatively large variances in medication profiles without adversely affecting therapeutic outcomes.
• Regulations are not so stringent as to stifle production of large varieties of whole plant medicines.

The good news is that movement towards satisfying these conditions are taking place. First, evolution in the cannabis industry in particular is creating greater awareness of and demand for (i) testing protocols and methods to ensure safety and accuracy of whole plant testing, as well as (ii) transparency of information regarding profiles of ingredients contained in whole plant products. Second, enormous resources have been flooding into research on whole plant products (medications, supplements, nutraceuticals, and foods) to better understand the nature of effects of whole plant substances on people’s health and wellness (45).

And third, regulators have been releasing new guidelines to address increasing demand for supplements and botanical drugs. As previously mentioned, Congress passed the Dietary Supplement Health and Education Act of 1994 (DSHEA), which decreased restrictions on the supply of dietary supplements (46). Subsequently, originally published in 2004 and updated in 2016, the FDA Center for Drug Evaluation and Research published its “Guidance for Industry: Botanical Drug Products” (47), which provides more flexibility for plant-based products seeking FDA approval and patent protection. According to Rutgers researchers (48),

"… [T]he guidance does not require full characterization of all extract components or full elucidation of their interactions, and may tolerate some variation in the final composition of the botanical drug. Although botanical drugs are not likely to be protected by the composition of matter patents used to protect NCEs [new chemical entities], they can be well protected by method of use or preparation patents. Botanical drugs are considered relatively safe from generic competition because a generic is required to be bioequivalent to the approved botanical drug."

Finally, “since 1999, WHO has published four volumes of WHO monographs on selected medicinal plants … to regulate herbal medicines and ensure their safety, efficacy and quality…” (49).

New Regulations

The regulatory environment in the US healthcare industry is largely determined by the FDA, which, in turn, is predominantly influenced by the needs of the pharmaceutical industry (pharma). Pharma has developed under the umbrella of the magic bullet paradigm, which, as discussed earlier, is based on the use of isolates and has evolved to focus on synthetics. Unfortunately, this environment is antithetical to the development of whole plant medicine. As previously discussed, whole plant medicine is based on the use of combinations of natural products, which work together to generate joint outcomes. This paradigm is problematic in the current environment for several reasons.

First, multi-compound extracts do not fit into the FDA approval process mold, which means it’s generally not feasible to secure FDA approval for such products. There are myriad factors contributing to the infeasibility of patenting whole plant products in the current environment, including the lack of product standardization; the need to use FDA-approved sources of products, which, in particular, makes development of qualifying cannabis products impossible;50 the difficulty in characterizing interactions across multiple compounds; the personalized nature of whole plant medication, meaning different patients require different compositions and frequencies of dosing; etc.

Yes, the FDA did attempt to address the complexities of whole plant products by issuing its Botanical Drug Development guidelines in 2004, which it subsequently updated in 2016. However, these guidelines do not successfully address the complexities of whole plant products. Since their inception in 2004 to date, a total of two botanical drugs have been approved by the FDA (51).

Yet without FDA approval, doctors will generally not prescribe whole plant products, nor will health insurance plans reimburse costs of medications. As such, patients cannot obtain recommendations or guidance on the use of whole plant products from their doctors, nor can they afford to use them regularly to maintain health and wellness. That fact the only two botanical drugs have achieved FDA approval provides clear evidence that efforts by the FDA and US government to make high quality whole plant products available to patients has been unsuccessful.

Second, the public goods nature of whole plant medicine creates difficulties for developers to invest in bringing new unprotected products to market. Consider, first, the traditional pharmaceutical industry paradigm: A new synthetic compound that a company develops into a medication is similar to other medications already existing in the industry, but it is also different from other compounds in some novel way. It is this novelty that enables the company to patent the synthetic compound. As the company develops its new patented substance, it creates new knowledge about how the product works on the body. Some of this new knowledge applies generally to other compounds in the industry, and as such, the innovating company generates new information that benefits everyone else in the industry. However, enough of the new information the company generates is specific enough to the new, patented compound that others cannot directly benefit. It is this specialized information, together with the patent on the compound, that enables the company to generate a profit on its investment in developing the new medication.

Now consider the whole plant medicine industry. The appeal of whole plant medicine is that it is natural, where plants and people have evolved together over the millennia to be compatible with one another. Yet, because plants are natural, they generally cannot be patented. As such, all new knowledge generated by a company who invests in bringing a new whole plant product to market will be freely available to everyone else. If the company brings a product to market and charges a high enough price to recover the costs of its investment, it will quickly be undercut by an imitator: a new competitor will use the freely available information to copy the original company’s product, yet be able to sell the same product at a lower price, since the imitator doesn’t have to recover the costs of the original research that went into creating the product. Thus, under the current regulatory scheme, investments in bringing new whole plant products to market cannot be easily recovered (52).

The third problem with the current regulatory environment as it relates to whole plant medicine is the murkiness in the regulations surrounding their development and sale.53 The lack of clarity makes it difficult for market participants to develop and sell new products.

In short, the FDA must adopt new regulations that:

• Facilitate the supply of whole plant medicines that are amenable to both physician recommendation and guidance, as well as health insurance reimbursement.
• Enable companies to profitably develop and sell safe and effective whole plant medicines.
• Provide clear guidance ensuring that safe, effective, and clearly and accurately labeled whole plant medications can be profitably brought to market.

Putting It All Together

Whole plant medicines are different from traditional pharmaceuticals in that they’ve been used generally safely and often effectively by billions of people over thousands of years.

The current generation of Western healthcare providers has been rigorously trained in the old, one drug, one target paradigm. It’s incredibly difficult to change a mindset, especially in those who have been so well-trained and established in alternative mindsets. The transitioning that’s already taking place toward combination therapies is a step in the right direction. In addition, the cannabis community is making great efforts and strides to educate healthcare professionals and patients about the endocannabinoid system, together with the complexity it entails. Finally, widespread patient adoption is forcing the healthcare community to address the use of whole plant medicine or risk losing patients. As activity in whole plant product markets continues to gain momentum, new mindsets are taking hold. A critical mass will soon be achieved, especially as science and technology continue their rapid march forward.

The two most ornery requirements for the whole plant medicine transition to succeed are proof of efficacy and standardization of supply. I believe the needs of a large majority of whole plant patients will be met before more stringent proof of efficacy and standardization of supply have been achieved, by requiring full accuracy and transparency of ingredients contained in whole plant medicines. Eventually, researchers will better understand the impacts of small variations in medications on patient outcomes, and more producers will be able to achieve sufficient standardization of supply. At that point, remaining patients for whom it is imperative to establish proof of efficacy and consistency of supply will have their needs met.

Currently, there are two routes to market for whole plant medications: the dietary supplement market and the botanical drug market. Figure 4 provides a side-by-side comparison of features relevant to users of whole plant products for these two markets, plus the prescription (human) drug market. The comparison shows that the burden of bringing a new dietary supplement to market is quite low, leading to huge numbers of supplements currently available. Consumers benefit from the wide variety and relatively low prices of supplements that are enabled by the low barriers to entry. However, consumers are afforded no guarantees that supplements are either safe or effective. It makes sense, then, that the FDA would want to provide consumers a safer alternative for whole plant products – namely, FDA-approved botanical drugs – than that offered by the supplements market. However, since only two products have made it through the botanical drug approval process, it’s clear that the botanical drug requirements simply do not work.

Figure 4

What patients need from regulators right now is to create an environment in which patients can access whole plant medications that are safe (accurately tested and labeled), effective, affordable, and profitable to supply. Accessible means doctors will prescribe, affordable means health insurance will reimburse, and profitable to supply means a large variety of products will be brought to market.

In truth, there are two submarkets of patients at issue. One submarket involves patients seeking whole plant products to address non-critical health conditions – that is, health problems that don’t significantly impede quality of life) – such as sleep, pain, or mood. The other submarket contains patients seeking to address critical health conditions, such as cancer, epilepsy, or intractable pain. For patients in the first submarket, small variations in profiles of ingredients from one bottle of medication to the next are generally acceptable, as long at the contents of each bottle are clearly and accurately labeled.

For the non-critical submarket, then, regulators must establish guidelines that:

• Provide clarity in and ensure enforcement of regulations.
• Establish and enforce regulations requiring strict testing and labeling protocols to provide patients and providers safe products with accurate and transparent information on product contents.
• Provide product certification amenable to physician recommendation for whole plant products.

Certification serves as a barrier to entry, which could enable suppliers to profitably supply products in the market. The certification process should be stringent enough as to differentiate safe products from the rest, but not too stringent as to prevent suppliers from bringing new products to market. While whole plant products may be relatively expensive when used regularly, trying to support a system in which non-critical products are insurance-reimbursed is simply not tenable without introducing requirements that would drive up costs of supply, and thus prices to consumers.

For patients in the critical submarket, however, consistency from dose to dose, availability of supply, and proof of efficacy are all essential. Regarding efficacy, FDA approval under the Botanical Drug Guidelines requires product manufacturers to conduct random-controlled trials on hundreds of patients, using standardized dosing across patients, to establish product efficacy. However, standardized dosing is not appropriate for whole plant medicine, due to its personalized nature. As described earlier, whole plant medicine is individually formulated to address patients’ particular systems (genetics, lifestyle, environmental, etc.). Establishing proof of efficacy for whole plant products will thus require manufacturers to formulate whole plant treatments and/or dosing schedules that address the idiosyncratic needs of each patient. As such, requiring traditional randomized control trials for FDA approval of Botanical Drugs has likely prevented companies from going down this route.

The good news is that new methods for establishing proof of efficacy of medical treatments across heterogeneous patients are gaining momentum. Specifically, rather than randomizing periods of treatments across patients, N-of-1 Trials randomize time periods of treatment for a given patient.54 In other words, patients serve as their own control. N-of-1 trials provide the perfect mechanism for manufacturers to establish efficacy of whole plant medicines. The costs of establishing efficacy will increase the product development costs, and thus patient prices. However, once efficacy has been established, doctors should be willing to prescribe, and insurance companies should be willing to reimburse, thereby making them affordable to patients for regular use.

For the critical submarket, regulators must establish procedures for ensuring efficacy:

• Regulators must provide an alternative path to FDA approval that facilitates physician recommendation and insurance reimbursement for whole plant products. One possibility is for the FDA to accept evidence from N-of-1 trials in lieu of that from traditional randomized control trials.

Acknowledgements

I’d like to thank Caleb McClain for his tremendous help in enabling me to clarify my thoughts.

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About the Author

Ruth Fisher, PhD, is a systems design researcher and analyst. She analyzes markets to determine how environments shape outcomes. She is co-founder of CannDynamics, Inc., and author of The Medical Cannabis Primer and Winning the Hardware-Software Game: Using Game Theory to Optimize the Pace of New Technology Adoption. Dr. Fisher has worked in the technology and healthcare sectors on behalf of technology companies, early-stage researchers, physicians, and technology start-ups.