• Path of Traditional Drug Development
• Feedback Drives Evolution
• Cannabis Has Greater Potential Than Most Drugs
• Drug Development Filters

A very clear pathway for the development and use of new therapeutics has existed for half a century now, and Cannabis’s Schedule I status has largely prevented it from traveling down that path. As a result, most people would probably agree that the development of cannabis’s therapeutic potential has been hampered, and in some sense, it surely has. At the same time, however, unlike most other therapeutics, medical cannabis has simultaneously existed in two separate spheres of society, the traditional medical healthcare sector and the whole plant medical cannabis sector. And while progress within the traditional medical sector has been hampered, progress within the cannabis sector has proceeded at an accelerating pace, precisely because cannabis has not played by the rules of mainstream society. One might even goes as far as to say that in certain respects, the extra-legal nature of cannabis could very well result in cannabis’s potential being reached more quickly than if it had been integrated into mainstream society decades earlier.

Path of Traditional Drug Development

The time path of new drug development in the US was established over the course of the first seven decades or so of the 20th Century.^[1]

Traditional drug development proceeds along a series of sequential stages (see Figure 1), briefly described as follows. New substances start in the lab, where researchers identify and investigate substances that address dysfunctions in the body. Once researchers have established a compound’s nontoxicity and ability to induce positive outcomes in vitro and in vivo,^[2] they undertake clinical studies. The clinical studies, which are conducted in four phases, have been carefully designed to be cost-effective yet reliable, that is, they draw on relatively modest numbers of patients to establish safety and efficacy of the new therapeutics. After a drug successfully passes through the four stages, the FDA generally approves the drug for a specific use case.^[3]Once FDA approval has been achieved, doctors start prescribing the new drug to patients with the specific symptom or condition for which the drug was approved. Over time, doctors may expand their scope of prescription to include off label (“secondary”) uses, such as a prescribing to a wider variety of patients with the same use case or prescribing to patients with other use cases the drug has been found to address.^[4]

Figure 1: Path of Evolution of Traditional Drug Development and Use 

Feedback Drives Evolution

The development of new drugs, together with the achievement of their full potential for improving health and wellness in diverse patient populations, is an iterative process. As with any such process, new drug development and use involves the ongoing collection of new information about effects, which is then used to hone development and use. This back and forth process is captured by the nested arrows in Figure 1, and the ongoing nature of these feedback effects are captured by the extended length (i.e., over time) of the rectangles in the Figure for each stage of the process. In short, feedback drives evolution. What this means is that the greater the depth, breadth, and speed of new information collected, the faster will be the realization of the potential of new drugs.

Cannabis Has Greater Potential Than Most Drugs

Before moving on to a discussion of the drug development and use process for medical cannabis, there’s an important point of distinction between traditional drugs and cannabis that warrants mention. Cannabis is different from most traditional drugs in that it has a much wider breadth of potential applications. The reasons for this are two-fold. First, while traditional therapeutics tend to involve single active compounds, cannabis encompasses a vast collection of hundreds of different compounds, with a vast array of potential applications. And second, traditional therapeutics tend to have very targeted mechanisms of action – single pathways. Cannabis, on the other hand, involves compounds that are highly promiscuous, that is, they act through many different pathways.^[5] Furthermore cannabis acts on a system in the body, the endocannabinoid system, that’s responsible for moderating the effects of all other body systems. In other words, the power of cannabis lies in the ability of many different combinations of cannabis compounds to work together through many different mechanisms of action to address many distinct areas of dysfunction in the body. In short, the potential of cannabis to improve health and wellness is vastly greater than that for most other traditional therapeutics. 

Drug Development Filters

Back to the drug development and use process. The traditional process involves two notable filters. First, while the successive stages of new drug development have been purposefully crafted to provide a robust process for establishing safety and efficacy of new drugs, the relatively long time lags associated with moving through the successive processes – as opposed to conducting them concurrently – undoubtedly slow the overall pace of development. Clearly, the nature of the four clinical stages is such that they have to be run successively rather than concurrently, but my point is that the large time requirements slow the feedback process. 

The second filter involves the small numbers of patients who participate in clinical trials and initial stages of post-approval use. Researchers use well-designed patient counts in their clinical trials to minimize cost while maximizing probability of establishing safety and efficacy. Yet, these small numbers of study participants also reduce the depth and breadth of feedback provided during the drug development process, relative to the case in which larger patient groups are used. In other words, the use of larger samples of more diverse patients in the drug trials and in the initial stages of use would reduce the time needed to achieve the full potential of new drugs. 

Again, there’s very good reasons for having these two filters in the traditional drug development process, but they nonetheless increase the time needed to generate the feedback needed to realize a drug’s full potential.

The evolution of medical cannabis development and use has proceeded along a very different path than that for more traditional therapeutics. I believe the differences in evolutionary paths is leading the potential of medical cannabis to be achieved much more quickly than it would have been, had the developmental process moved along a more traditional path. This more rapid pace of drug evolution in cannabis is due to the fact that the two filters present in the traditional drug discovery process have largely been absent in cannabis.

First Filter: Successive Stages in the Process

Let’s start with the first filter, the successive paths from pre-clinical experiments and studies, then to clinical trials, and culminating in patient use. Under this traditional path, research drives (i.e., determines) use. With cannabis, on the other hand, use has largely driven research (see Figure 2). Cannabis was introduced into the West during the 19th Century before drug approval requirements had been established. Consequently, when cannabis was introduced into society, doctors immediately starting prescribing use for patients, while researchers concurrently started studying its workings in the body. Notably, subsequent research was largely driven by the effects observed in patients who were using cannabis therapeutically (and recreationally).^[6]

During the mid-to-late 20th Century, patients used cannabis from illicit sources to treat a variety of symptoms and conditions.^[7] More recently, as more states have legalized medical use and then adult use cannabis, even larger numbers of patients have accessed both illicit and legal markets to treat a wide variety of symptoms and conditions.^[8],[9] The vast numbers of surveys and retrospective studies of patients that have investigated the symptoms and conditions for which patients use cannabis have surely driven much pre-clinical and clinical research into cannabis. In this case, cannabis patient use has driven research (see Figure 2).

Figure 2: Research Drives Use vs. Use Drives Research

Since use has driven – and continues to drive – research in cannabis, there are not the same time lags as those experienced in the development and use process for more traditional drugs. Instead, the coincidental nature of research and use has led to a horizontal, rather than a vertical, feedback process (as illustrated in Figure 3). This concurrence enables much more rapid feedback effects, which drive evolution of knowledge surrounding cannabis’s potential at a much more rapid pace than that which would have been achieved had cannabis developed along a more traditional (i.e., vertical) path.

Figure 3: Path of Evolution of Cannabis Drug Development and Use 

Second Filter: Constraints on Patient Use

The evolution of medical cannabis development is also avoiding the second filter on traditional drug development, that of constraining the numbers of patients involved in clinical trials and early stages of patient use. In particular, clinical trials for more traditionally developed drugs involve relatively small numbers of patients. Also, traditional developers achieve FDA approval for their drugs for particular dosage regimens, administration routes, pharmaceutical forms, indications, age groups, and/or categories of patients.^[10]Generally, doctors initially prescribe the new drug only for those patients and usage patterns for which the drug was approved. Over time, doctors may then start prescribing drugs for off-label use, such as for different patient groups or for different usage patterns. In short, relatively few patients have access to new drugs during development and shortly after approval.

Pharmaceutical versions of cannabis have indeed proceeded down the traditional path of development and use. Dronabinol and nabilone, synthetic THC, were FDA approved and available by prescription as of 1985, and they’ve been prescribed since then for their FDA-approved uses, that is, to treat HIV/AIDs and chemotherapy-induced nausea and vomiting (“CINV”).^[11],[12]  (The small number of cannabis pharmaceuticals is a case in point for the stymied development of cannabis therapeutics within the traditional drug development system.)

Despite the availability of these two pharmaceuticals, however, the development and use of cannabis has proceeded outside the bounds of traditional society down its own path. Whole plant cannabis has been used illicitly since it was banned in 1937, for the same indications for which synthetic THC was approved, as well as for many others, such as glaucoma.^[13] Legalization of medical cannabis was finally achieved, not through FDA approval, but rather, through lobbying efforts by large, grassroots movements of patients, caregivers, and other interested parties. The legalization of medical cannabis – thus far mostly prescribed, purchased, and used outside the traditional healthcare system – was eventually granted starting with California in 1996;^[14]followed by Alaska, Oregon, and Washington in 1998; Maine in 1999; and Colorado, Hawaii, and Nevada in 2000.^[15] As states started legalizing medical cannabis for a wide variety (dozens and dozens^[16]) of qualifying conditions, patient use started to explode. Throughout its decades of use, the illicit and newly legalized use of medical cannabis has involved caregivers working with patients and formulating products in a learning-by-doing environment, devoid of formal research into underlying mechanisms of action. 

Back in the traditional healthcare sector, by the early 2000s, it had been almost a decade since the ECS had been discovered, and pre-clinical and clinical research in the area had started to accelerate. Given this history of medical cannabis development and use as it existed outside the formal sector, though, it’s reasonable to conclude that while much patient use was almost certainly driven by medical research (i.e., research drove use), the effects tended to move more in the other direction, that is, much of the research on cannabis was surely being driven by reports of patients’ experiences (i.e., use drove research). 

We see, then, that relative to what would have occurred within the traditional drug development process, as more traditional research into cannabis has progressed, much larger numbers of patients have been concurrently using many different combinations of cannabis compounds, in many different forms of use, and for a wide variety of indications. The relative proliferation of patient use, despite the lack of a good understanding of how cannabis generates it effects, is due to several factors. First, cannabis products don’t need FDA approval before being allowed on the market, which has led to wide availability of an enormous variety of products. Second, the conditions that states choose to include as qualifying conditions under their medical cannabis programs are not restricted to FDA-approved uses. In Illinois, for example, patients can petition the state to add conditions to the registry,^[17] and the state currently lists 35 conditions for which patients can qualify for medical cannabis use. ^[18] Third, patients don’t need a prescription for each product or use, which has increased volume and variety of product use. That is, once patients qualify for medical use, they may purchase and consume any form of use with any potency, up to state-determined limits. For example, under Illinois’s medical cannabis program, patients “can purchase up to 71 grams or 2.5 ounces of cannabis in any 14-day period.”^[19] Fourth, any person in an adult use state who wants to use cannabis therapeutically for the use case of his or her choice can simply purchase cannabis from adult use dispensaries. In other words, the medical uses of cannabis are not limited only to qualified patients or qualifying conditions for a given state. 

This expansive nature of cannabis use has enabled researchers to collect a much larger depth and breadth of information – using, for example, retrospective studies, surveys, and tracking data – much more rapidly than otherwise. Though we are still in the early stages of understanding of cannabis, the path of discovery and development has been much more rapid than would have been possible for more traditional drugs. As a result, cannabis’s potential may come to be achieved much more quickly than if it had proceeded down the traditional path of development.

Impact of Status I Classification

Of course the speed of progress along the traditional research pathway for medical cannabis has been hampered by its Schedule I status, which has created barriers to gaining approval from regulators and barriers to accessing funding and good quality cannabis samples to conduct their research.^[20] As long as cannabis remains a Schedule I drug, these barriers will continue hamper progress down the traditional path for developers seeking FDA approval for cannabis therapeutics. Nonetheless, medical cannabis products will continue to be studied and used outside the formal system, moving us closer to achieving cannabis’s potential. 

References 

^[1] Fisher R (2023, Dec 5). Is Medicine Undergoing A Paradigm Shift From Single to Combination Therapy? The Case for Whole Plant Medicine. AJEM. https://www.endocannabinoidmedicine.com/features/is-medicine-undergoing-a-paradigm-shift-from-single-to-combination-therapy-the-case-for-whole-plant-medicine/

^[2]Step 2: Preclinical Research. (2018, Jan 4). FDA. https://www.fda.gov/patients/drug-development-process/step-2-preclinical-research

^[3] Step 3: Clinical Research. (2018, Jan 4). FDA. https://www.fda.gov/patients/drug-development-process/step-3-clinical-research

^[4] Rusz C et al (2021). Off-Label Medication: From a Simple Concept to Complex Practical Aspects. Int. J. Environ. Res. Public Health. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508135/pdf/ijerph-18-10447.pdf

^[5] Raup-Konsavage WM (2023, Mar). Special Issue: Therapeutic Potential for Cannabis and Cannabinoids. Biomedicines. https://ncbi.nlm.nih.gov/pmc/articles/PMC10045812/

^[6] Grinspoon L (2005, Aug 16). History of Cannabis as a Medicine. MAPS. https://maps.org/research-archive/mmj/grinspoon_history_cannabis_medicine.pdf

^[7] Grinspoon L (2005, Aug 16). History of Cannabis as a Medicine. MAPS. https://maps.org/research-archive/mmj/grinspoon_history_cannabis_medicine.pdf

^[8] Mahabir VK et al (2020). Medical cannabis use in the United States: a retrospective database study. Journal of Cannabis Research. https://jcannabisresearch.biomedcentral.com/articles/10.1186/s42238-020-00038-w

^[9] Illinois allows patients to submit petitions to gain approval for access to medical cannabis to treat specific conditions. Currently, there are 35 qualifying conditions for medical cannabis in Illinois. Medical Cannabis Patient Registry Program. IDPH. https://dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis. Illinois Medical Marijuana Card. Illinois Cannabis Information. https://illinoiscannabis.org/medical

^[10] Rusz C et al (2021). Off-Label Medication: From a Simple Concept to Complex Practical Aspects. Int. J. Environ. Res. Public Health. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8508135/pdf/ijerph-18-10447.pdf

^[11] Dronabinol (2023, Sep 4). StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK557531/

^[12] Nabilone (2021, Oct 2). LiverTox: Clinical and Research Information on Drug-Induced Liver Injury. https://www.ncbi.nlm.nih.gov/books/NBK547865/

^[13] Grinspoon L (2005, Aug 16). History of Cannabis as a Medicine. DEA statement. https://maps.org/research-archive/mmj/grinspoon_history_cannabis_medicine.pdf

^[14] Grinspoon L (2005, Aug 16). History of Cannabis as a Medicine. DEA statement. https://maps.org/research-archive/mmj/grinspoon_history_cannabis_medicine.pdf

^[15] State Medical Cannabis Laws. (2023, Jun 22). NCSL. https://www.ncsl.org/health/state-medical-cannabis-laws

^[16] Medical Marijuana Qualifying Conditions by State. (n.d.). Marijuana and the Law. https://marijuanaandthelaw.com/resources/medical-marijuana-qualifying-conditions-state/

^[17] Medical Cannabis Patient Registry Program. IDPH. https://dph.illinois.gov/topics-services/prevention-wellness/medical-cannabis

^[18]Illinois Medical Marijuana Card. Illinois Cannabis Information. https://illinoiscannabis.org/medical

^[19]Illinois Medical Marijuana Card. Illinois Cannabis Information. https://illinoiscannabis.org/medical

^[20] Cooper ZD et al (2021, Nov 28). Challenges for Clinical Cannabis and Cannabinoid Research in the United States. J Natl Cancer Inst Monogr. https://pubmed.ncbi.nlm.nih.gov/34850896/