Cannabis Drug Development: Intersection of Pharmaceutical and Cannabis Industry

The US medical cannabis industry is in a difficult position, conceptually straddling the line between recreational use and pharmaceutical drug development.

Cannabis pharmaceutical drug development would fit more neatly within the established scientific and prescribing models and, in that sense, would be better for clinicians and their patients. Although we will undoubtedly see an increase in the development of cannabinoid medications leading to better formulations, drug development takes a long time and is expensive.

Currently, there are very few FDA-approved cannabinoid medications available. Given federal guidelines that prevent implementation of cannabis treatments into mainstream medical practice in the United States, clinicians have their hands tied. As clinicians, we continue to struggle to make the current system work for our patients. Medical cannabis is what we have now.

Barriers to Cannabis Drug Development

One of the many reasons that drug development takes so long and costs so dearly is the level of evidence the FDA requires for medications to be marketed.¹ The FDA approves a drug for a series of human trials (phases I, II, and III) based on the totality of preclinical evidence (mouse or cell-culture data) and research that the drug developer may have performed. These human trial phases are carefully designed to prove the medication’s safety, dosing, and efficacy for a particular indication in humans. However, a few cannabis-specific details make the FDA approval process more difficult.     

First, cannabis is still illegal under federal law.² Although federal law is expected to change, it’s unclear what new legislation will look like. Although still illegal at the federal level, it’s possible to conduct cannabis research, although considerably more difficult, raising the question of why a company would perform the research.

Second, the existence of medical cannabis undermines financial incentives to do the research. At least for a cannabis company—and I’ve worked with a several—one question always arises: “Why spend the money to do the homework if we can just go to market?”

Third, the FDA requires that the product used in the phase III trial be the same as what will be marketed if approval is granted.¹ This isn’t easy to achieve with botanical products.

Cannabis Has Hundreds of Compounds

Lastly, the FDA pathway to approval is generally set up for a drug comprising only 1 chemical¹ (ie, aspirin is salicylic acid, Tylenol is acetaminophen, and Motrin is ibuprofen). Some medications that combine 2 or more substances remain viable for patent protection for drug makers who use off-patent (generic) drugs.³ This strategy may play a significant role for pharmaceutical companies that venture into cannabinoid medications.

It seems unlikely that current medical cannabis products will directly meet the evidentiary standard for medicines. However, companies that do the research will be able to develop combination medications that gain patent protection. The catch, however, is that combination medications only get a “hall pass” for preclinical trials if the individual constituent drugs are well-proven,¹ even then, the developer must repeat clinical phase trials. Only delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have been approved by the FDA, so only those chemicals would be given a “leg up.” To perform clinical trials with chemicals other than THC and CBD, separate trials would need to be conducted for each constituent—and in all the various permutations of the other constituents. For example, if a developer proposes a medication containing THC, CBD, cannabidiolic acid, and 2 terpenes, it would have to test all 5 separately or 120 combinations! That’s pretty unrealistic, complicated, and expensive.  

Synthetic Cannabinoids

Many pharmaceutical companies take an alternate approach by developing novel chemicals that mimic those of cannabis. This strategy makes the chemicals more readily patentable. Still, given the nature of cannabinoids and what we know from THC and CBD, it’s likely that these single chemicals will still fall short of the efficacy of plain old cannabis,^4,5 leading back to combination drugs and all that entails.

A Path Forward Requires Rescheduling and Regulation

So, what’s the path forward? First, the federal government must become serious about cannabinoid medicines.⁶ It must remove cannabis from a Schedule I or II listing and start funding deeper research into the potential benefit of cannabinoids via grants from the National Institutes of Health.

The federal government also needs to regulate medical cannabis nationally and, by doing so, “sunset” these regulations after a reasonably long time. For example, the government could provisionally approve products in the medical market for 10 years. After that time, the product would be moved to the recreational use market if the manufacturer has not completed the necessary steps required for drug approval by the FDA.            

Regulating cannabis in this manner will protect current patients from being marginalized either in a solely recreational use market or one that ceases to exist while pharmaceuticals are being developed. Furthermore, it would give cannabis companies time to meet the bar for drug development or refocus on recreational use products. Federal de-listing of cannabis encourages pharmaceutical companies to bring their vast resources and knowledge into the cannabinoid space with the promise of protected products once the development is completed.

Disclosure:

Dr. Tishler is President of the Association of Cannabinoid Specialists (ACS), an international nonprofit focused on health equity for patients. The ACS strives to bring human evidence–based treatment to patients by educating clinicians and lawmakers on the value, risks, and ethics of cannabinoid treatment. The ACS provides a range of educational materials to members and the public. For more information, please visit cannaspecialists.org