Taking a look back, we can see that the modern pharmaceutical industry evolved from more crude preparations and administration of natural product extracts. With consideration also given to what makes an effective therapeutic compound, it is interesting to think how the medicinal cannabis business will evolve through a similar lens.
The cannabis and hemp industries, a longtime taboo area at the never ending frontier of science, are now expanding at alarming rates. As we see individual states passing favorable legislation for medical and recreational cannabis, the Federal Farm Bill has opened the door for industrial hemp, and with it, a massive influx of cannabidiol (CBD) and CBD-infused products. While a large majority of these burgeoning business entities are pursuing extensive cultivation efforts to produce potent flower material and isolate products at a more expeditious and economical rate, perhaps there are other opportunities on the periphery that are worth investigating. This becomes more apparent if we look at the approach that the pharmaceutical industry took with natural products during its nascent stages; an approach that continues to produce blockbuster medicines today.
Prior to the evolution of the modern pharmaceutical industry, early biopharmacology involved the prehistoric use of plants, insects, animals, molds, and raw chemicals. Early healers understood that preparations and extracts of these materials had beneficial effects for people suffering from disease, or had psychological effects that were considered desirable. In the preindustrial age, these preparations contained a vast number of molecular components, which could cause unwanted effects including lethal toxicity. Many modern medicines are linked to these millennia-old remedies.
If we use the history of opium poppy (Papaver somniferum) as an example, we see that many elixirs were prepared by extraction with ethyl alcohol and water, and the cultivation of opium plants may be traced to Mesopotamia ca. 3400 B.C. Physicians in the 18th century recognized that use of the Papaver elixir had tonic effects on heart failure, asthma, and gastrointestinal illnesses. They also learned that attaining therapeutic doses of the underlying molecule required chronic consumption of morphine, which is the largest constituent of opium. Even then, this was considered deleterious.
In 1848, Georg Merck first separated and characterized Papaverine from opium. Papaverine is a benzylisoquinoline alkaloid and occurs naturally in opium at a concentration of 0.5%. Papaverine was rapidly recognized as beneficial for cardiac and pulmonary conditions. Demand for Papaverine rapidly outpaced the supply that could be obtained from biologic sources. This led to a quest to synthesize Papaverine from de novo sources. This synthesis was first successfully accomplished in 1879 and has had numerous improvements since then. The isolated molecule nonselectively relaxes smooth muscle in the body—smooth muscle being the only form of muscle in cardiac walls, blood vessels, pulmonary airways, and the wall of the intestines. Papaverine has a half-life of ca. 1 h. The use of oral preparations required that dosing be performed 6–10 times a day.
Subsequently, Verapamil was first synthesized in 1962, and while not a direct analogue of Papaverine, thermal degradation and methylation of the pyrrole ring of Papaverine gives the structure of Verapamil. Verapamil is also a calcium channel blocker. This is particularly significant given its tonic effects on smooth muscle and its primary use as an anti-arrhythmic. The take home point is that Verapamil was approved as an ethical drug and has produced more than $100 billion dollars in revenue since its approval.
Another example of drugs used for many centuries as a folk remedy is Digitoxin and Digoxin. Both are isolated from the flower of the Foxglove plant (Digitalis sp.). Digitoxin was used for heart failure and Digoxin continues to be used today, both for heart failure and as an anti-arrhythmic. Both are cardiac glycosides, which have extremely long half-lives: 3–5 days for Digoxin and 7–9 days for Digitoxin. Both molecules have very narrow therapeutic windows. The therapeutic dose and fatal dose of Digitoxin are almost identical. This has greatly limited the usefulness of either as a medicine.