Opportunities in the Evolving World of Cannabis-Based Pharmaceuticals

Cannabis-based pharmaceuticals represent the most promising and potentially valuable sector of the growing cannabis industry.

Although several drugs have been approved by the FDA, hurdles remain in generating the data and the safety information needed to meet strict clinical standards for approval.

Its clear that sound science and well-controlled clinical trials are needed in order to lead the way towards approved drugs and therapies.

To this end, research funds and areas of investigation are expanding, albeit more slowly than needed, both at the federal and private support levels. The most recent search of cannabidiol through the clinicaltrials.gov database showed 321 active and recently completed clinical studies and over 500 studies involving THC.

Several novel areas of investigation have recently surfaced, offering inroads to treatment of previous intractable diseases. As well, basic science and engineering are generating original compounds, formulations, and methods which may see applications in a greater range of use than previously identified.

The science behind the evolving world of cannabis-based pharmaceuticals will ultimately pave the way towards better, more effective treatments for a wide range of human conditions and disease. Here are a few interesting developments.

Cannabis-based therapeutics

To date there is one cannabis-derived and an additional three cannabis-related drug products approved by the FDA:

• Epidiolex contains pharmaceutical grade purified CBD, and is approved for the treatment of seizures associated with Lennox-Gestault syndrome or Dravet syndrome.
• Marinol and Syndros contain a synthetic analog of THC, dronabinol, and are approved for the treatment of anorexia associated with AIDS patients.
• Casamet contains the active ingredient nabilone, which is a structurally similar synthetic analog of THC.

Despite developments in all areas, including federal hemp legalization, no other cannabis-based pharmaceuticals are currently approved for use.

The FDA approval process for cannabis therapeutics

The 2018 Farm Bill effectively removed hemp from the controlled substances act, making cannabis technically legal — provided it contains < 0.3 percent THC by dry weight. The Farm Bill also explicitly preserved the authority of the FDA in regulating cannabis products and derived compounds, including hemp-derived CBD.

CBD and other cannabis compounds must adhere to the same regulatory scrutiny as any other substance of potential therapeutic use:

• Premarket approval is required by researchers investigating a potential new drug, who must work with the FDA and submit Investigational New Drug Application (IND).
• Clinical research protocols and methods for production and delivery of the drug candidate must be evaluated by the FDA at regular intervals throughout investigations to ensure patient safety and to monitor potential side-effects.

Although CBD has been removed from the CSA, investigations on remaining Schedule 1 cannabis compounds including THC require additional monitoring by the DEA, which includes approved drug source materials, site visits, and other measures.

Ultimately, the compete application must be submitted for FDA review, and definitive data regarding the safety, side-effects, cross-reactivity, and therapeutic effectiveness must be comprehensive and clear.

Therapeutic potential for cannabis compounds and formulations

Cannabidiol (CBD) has witnessed an epic boom of popularity in everything from mood remedies to immune boosters. Medically speaking, what are the real prospects for CBD beyond the FDA-approved Epidiolex for treatment of seizures?

Chronic pain is an often-cited area for CBD therapeutics, and clinicaltrials.gov lists a number of clinical studies involving chronic pain syndrome, neuropathic pain, traumatic pain, and a host of other indications. Insomnia is also an area that has seen interest, as well as inflammation, mood disorders, and anxiety.

There is some evidence for Parkinson’s, IBS, Crohn’s, Alzheimer’s, and other wide-ranging disorders as well. However, in order to substantiate the effectiveness of CBD for these applications, clinical research into effective dosage, safety and purity of formulations, and other qualities require better definition. In a broader context, more research is needed to better decipher the therapeutic targets and mechanisms of action of CBD.

The same can be said for THC and other cannabinoids and terpenoids. Pain, PTSD, depression, and sleep disorders all have been therapeutically associated with THC, but these supporting claims require further clinical evidence to achieve FDA approval and patient use. Even multiple types of Cancer have shown sensitivity to THC in preliminary studies, claims which now await more rigorous analysis.

Science and engineering are leading the way in generating new cannabis compounds and applications

Beyond garnering convincing clinical data to propel preliminary therapies forward towards approval, cannabinoids and terpenoids can potentially serve as lead compounds in the development of a broader range of effective and productive therapeutics. This approach has gained the interest of a host of groups looking into engineering the structure, activity, and production of cannabis-derived compounds. Four of the key areas being investigated are:

1. Increasing the solubility of organic compounds or extractions

As a result of the organic, insolubility character of cannabinoid and terpenoid extractions, many tincture and formulations are oil-based and are limited in the range of substances which can be coupled for delivery. This extends to a range of consumer markets, where insolubility has been a problem for infused drinks, consumables, and other product formulations.

A patented aqueous phyto recovery process have been used recently as a way to recover water-soluble phytochemicals from pant extracts, releasing oil components without disrupting the molecules of interest. Such a method may be useful for removal of components which cause insolubility in aqueous solutions, while enriching for water soluble compounds.

Glycosylation is another approach shown to infer solubility to molecules by attached of a sugar group, which is subsequently metabolized without effect on the activity of the compound itself.

Supplements or excipients may prove effective as well in solubilizing key extraction components, while allowing filtration and removal of background materials. As a typical process in the pharmaceutical development pipeline, such formulation research is likely a necessary step in bringing any new cannabis compound closer to clinical use.

2. Increasing the bioavailability of bioactive compounds

By increasing the solubility profile of a key molecule, compound, or formulation, the bioavailability profile also changes. Insoluble compounds present in consumables are absorbed by the gut at a delayed rate and lower efficacy relative to other routes of entry. Increased solubility may enhance absorption, producing faster onset and more precise dosing parameters.

3. Enhancing and modifying the structures of cannabis compounds

Scientists, bioengineers, and industry groups have begun to engineer model organisms to synthesize cannabis compounds. Common yeast has been modified to produce THC from the sugar galactose, as well as for production of CBD and other interesting albeit rarer cannabinoids. The theory is that large scale fermentation of these recombinant yeast will allow faster and simpler production of molecules and compounds.

Taking a few steps further, the biosynthetic genes required for cannabinoid production in yeast can themselves be altered, theoretically yielding cannabinoids that don’t currently exist in nature. The production of an array of these unnatural cannabinoids, a feat not lost on readily available yeast production methods, may lead to the ability to screen compound libraries for therapeutic properties – those that might be expected and others that are completely novel.

4. Tuning the mode of action of cannabis compounds

Better, more complete research into the therapeutic targets and biological processes affected by cannabis compounds will lead to the understanding of more precise formulations and modes of action.

Teasing out the underpinnings of the “Entourage Effect” will allow more precise combinations of compounds that in turn produce more targeted effects. Specific extraction techniques tailored directly to the cannabis plant strain or chemotype can provide the specific compound profiles necessary to elicit therapeutic effects.

Finally, it goes without detailed discussion that better understanding of the therapeutic target(s) will allow better screening and compound identification using recombinant approaches and synthetic methods such as those described above.

The significance of cannabis research and therapeutics

The range of potential therapeutic applications of cannabis is staggering, and research and industry efforts will continue to push the frontier of pharmaceutical development.

The timing could not be more important, as studies have begun to show effectiveness of cannabis in treating the heroin epidemic by dampening the threat of relapse from addiction.

For these and other reasons, new inroads into cannabis research and development mean great opportunities for the world of pharmaceutical science and therapeutics.

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Updated June 2021