The first isolation and characterization studies in the cannabinoid area began in England with the work of Wood, Spivey and Easterfield in 1896 using Cannabis indica (Wood et al. 1896). As would be the case for decades of future Cannabis research, obtaining lipophilic cannabinoids as crystalline solids from natural sources was a frustrating challenge. However, these workers eventually purified a substance as its acetate which upon hydrolysis gave a phenolic compound that they named cannabinol. As so often happened in this natural products area, ongoing progress in cannabinoid research was then abruptly stopped for decades. In the early 1930’s, Robert S. Cahn again resumed work on cannabinol, isolating it from the same earlier source Cannabis indica. Cahn also prepared cannabinol derivatives, testing them with color forming reactions and culminating in a close yet incorrect structure prediction for cannabinol (Cahn 1933). However, sustained research and success on cannabinol and other cannabinoids waited for almost another decade and a unique Cannabis source as well as the creativity of an academic natural products chemist whose reputation was already gaining momentum.

Harvard trained organic chemist Roger Adams began his extraordinary career at the University of Illinois Chemistry Department in 1916. By 1939 Adams was already in mid-career, directing an extremely active group of a dozen or so graduate students producing a steady stream of seminal papers in prestigious publications like the Journal of the American Chemical Society. Regarding natural products, Adams fearlessly took on more challenging projects with the high risk of failure but also potentially large reward. Many of these studies had important agricultural benefits. Relevant for this discussion, in 1939 Adams started another marathon natural products project which changed Cannabis chemistry forever.

In 1939, Adams was approached by the Treasury Department Bureau of Narcotics (today’s equivalent is the Drug Enforcement Administration) with an interesting proposition; namely, to carefully examine the still largely unknown chemistry of Cannabis. Almost certainly, Adams was selected because of his celebrated success in natural products and this proposal would have clearly appealed to him for several reasons. First, the briefly explored Cannabis chemistry had been all but abandoned years before and there were still many intriguing and unanswered questions. Secondly, the Treasury Department provided Adams with permission to work in this increasingly government supervised area. At that time, Cannabis was heavily regulated by the Marijuana Tax Act (MTA) of 1937 which did not prohibit it but still imposed expensive fines and possible imprisonment for violations, thereby strongly discouraging Cannabis use (Pisanti and Bifulco 2017). Finally, the Narcotics Laboratory offered to provide Adams with all the Cannabis raw material that he would need. Specifically, Minnesota wild hemp (Cannabis sativa) was chosen as the botanical source for this renewed Cannabis research. Also known as “Ditch Weed,” this plant had been well described in an earlier classic botanical treatise (Oswald and Boss 1918). This annual seed propagated Cannabis variety known for its strong fiber content grew freely without cultivation along roads and rivers in Minnesota. Curiously, Oswald and Boss regarded this wild hemp as only an obnoxious weed, third on their list of several dozen botanical offenders and they provided specific guidance about its eradication. However, Minnesota wild hemp was a very practical plant choice for Adams’ research at that time. With World War II looming and access to valuable fibers from the Pacific rim curtailed, the government was actively growing large amounts of this hardy fiber producing hemp in midwestern states including Minnesota.

The details regarding the Minnesota wild hemp harvesting and initial large-scale processing are technically fascinating and partially outlined below, excerpted from the Experimental section of Adams’ first cannabinoid paper (Adams et al. 1940f):

“The hemp used in these experiments grew wild in Minnesota during the season of 1938. It was cut in August, after flowering had begun but before seed had “set” in the female tops. It was stored for 6 weeks in a room where a fan assured circulation of air in order to dry it completely. No molding occurred. The material was then beaten and shaken to remove the course stems which amounted to about one third of the total dry weight. The stems were discarded and the relatively fine material that remained was extracted with 95% ethanol …”.

The above procedure was performed at the Treasury Department Narcotics Laboratory in Washington D. C. on a 40 kg hemp batch along with its large volume ethanol extraction process. The ethanol extracts were then concentrated to a small volume by an elaborate distillation system followed by petroleum ether dilution, several water washes and final distillation to yield about 100 g of a purified red oil. This red oil, so frequently referred to in Adams’ many subsequent papers, was supplied to his University of Illinois laboratory. While the Minnesota wild hemp extraction operation was ongoing, Adams no doubt was pouring over the earlier Robert S. Cahn 1930’s publications as a valuable resource for developing his own technical strategy of cannabinoid isolation from the Minnesota wild hemp red oil. Based on that research, Adams was very aware there was little chance of directly crystallizing low melting cannabinoids themselves from the red oil but often, higher melting derivatives of them could be. Here is where Adams first encountered an immediate and annoying technical problem. In contrast to the earlier results of Cahn, Adams could not obtain a crystalline cannabinoid acetate or p-nitrobenzoate derivative from the Minnesota wild hemp red oil. Devoting only one dispassionate sentence of his first paper to this inconvenient setback, Adams was not terribly surprised about the outcome. Cahn had utilized a distinctly different Cannabis source for his earlier work, containing either different cannabinoids or differing amounts of them. This technical reversal challenged Adams’ creativity, but it also provided him with a wonderful chance for invention.

Adams’ account does not indicate the number of any failed attempts, but he finally reported success in isolating a significant amount of a bis-3, 5-dinitrobenzoate cannabinoid derivative from the Minnesota wild hemp red oil. Gentle ambient temperature ammonolysis of this substance with ammonia in toluene and typical organic reaction workup afforded a pure compound as a pale yellow resin which Adams named cannabidiol. He later developed an improved cannabidiol bis-3, 5-dinitrobenzoate derivatization procedure “where 45-50% of the purified red oil can be shown to be cannabidiol” (Adams et al. 1940e) and was also awarded a US patent (Adams 1942) for his novel process. As sometimes happens in chemistry, the initial failure to reproduce the earlier literature result was truly an inventive opportunity for Adams. Using all the chemistry and biology tools available to him in 1940, Adams characterized cannabidiol as thoroughly as possible, noting that it was non-intoxicating (Russo 2017) as well as decorated with an asymmetric carbon framework as evidenced by its significant negative optical rotation. Unfortunately, this stereochemistry complexity confounded Adams’ ability to derive a completely accurate structure for cannabidiol (Adams et al. 1940a). This frustrating structure conundrum for cannabidiol took another two decades to ultimately resolve as structure 1 (Scheme 1) by the essentially simultaneous discovery of Mechoulam (Mechoulam and Shvo 1963) and Santavy (Santavy 1964). As a precursor to this achievement, in his paper Mechoulam credited Adams’ “masterly investigations” and “substantial progress” in the Cannabis field. However, Adams’ exploration of the Minnesota wild hemp red oil continued and proved to be even more rewarding. He was also able to isolate from it both the known inositol derivative quebrachitol as well as the earlier reported cannabinol whose structure Adams conclusively proved to be 2 (Scheme 1) by unambiguous total synthesis (Adams et al. 1940d). Remarkably, the most extraordinary cannabinoid chemistry discovery by Adams in this already productive Minnesota wild hemp exploration was yet to come.

Based on the above results, Adams had essentially isolated all the major constituents from this bountiful midwestern botanical source. However, Adams was soon to discover at the bench a most amazing reaction involving cannabidiol. Although he was not able to decipher the complete structure of cannabidiol, Adams did establish that it contained an isopropenyl moiety proximate to several resorcinol hydroxyl groups. Treating cannabidiol with a number of different acidic reagents, Adams was easily able to force one of the resorcinol hydroxyls to ring close on the nearby isopropenyl tertiary carbon position, forming several optically active cyclized products, each with a dimethylpyran ring analogous to that of cannabinol (Adams et al. 1940c). Adams simply described these products as putative tetrahydrocannabinols. Having nearly the same complicated carbon skeleton motif as cannabidiol, Adams was again not able to completely deduce the exact structure of these tetrahydrocannabinols but believed that they were very likely olefin isomers of each other. Furthermore, these cyclized products were found to be intoxicating. Adams also prophetically suggested that some tetrahydrocannabinol would eventually be found naturally in Cannabis itself (Adams et al. 1940b). Two decades later in 1964, Mechoulam (Gaoni and Mechoulam 1964), isolated the physiologically active (intoxicating) delta-9-tetrahydrocannabinol (3, Scheme 1) from Cannabis, confirming the exact structure proposed by Santavy (Santavy 1964).