The early history of cannabinoid research
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CANNABIS AND CANNABINOIDS
The early history of cannabinoid research Giovanni Appendino1 Received: 2 August 2020 / Accepted: 14 September 2020 © The Author(s) 2020
Abstract Studies on cannabinoids that predate the identification of ∆9-THC as the intoxicating constituents of recreational cannabis by Raphael Mechoulam in 1964 are reviewed, critically analyzing the controversies and faux pas that have characterized the early research in this area. Significant contributions to the elucidation of the signature molecular scaffold of cannabinoids were provided by some of the finest organic chemists of their generation, like Roger Adams and the Nobel laureate Alexander Todd, and important studies of preeminent scientists like Robert Sidney Cahn and František Šantavý also deserve mentioning. The results of these studies include the structure elucidation of cannabinol (2a), and the preliminary structure elucidation of cannabidiol (CBD, 3a) and various semi-synthetic tetrahydrocannabinols (THCs). A comparative analysis of the contributions to the area by Adams and Todd highlights the transition between two generations of organic chemists, and the profound influence that the development of chromatographic methods of purification and of spectroscopic techniques of structure elucidation have played on the development of organic chemistry. Keywords Cannabis sativa L. · Natural products · Cannabinoids · History of chemistry
With some notable exceptions like the heliocentric theory, radioactivity, and evolution, the generally tortuous This peer-review paper belongs to the Topical Collection Cannabis and Cannabinoids, edited by Vincenzo di Marzo and Gennaro Marino, and originated from the Conference “Cannabis and Cannabinoids: History, Uses, and Socio-Economical Implications of a Controversial Plant” organized by Vincenzo Di Marzo (Coordinator), Gennaro Marino, Jacopo Meldolesi, Daniela Parolaro, and held on December 20, 2019, at the Accademia Nazionale dei Lincei in Rome. * Giovanni Appendino [email protected] 1
Dipartimento di Scienze del Farmaco, largo Donegani 2, 28100 Novara, Italy
and often colorful way in which scientific knowledge can emerge from random observations, faux pas, and serendipitous discoveries is largely overlooked in modern discussions, remaining relegated to specialized audiences or becoming summarized in a series of “Eureka moments” of inspiration by a single talented scientist. Raphael Mechoulam is considered the father of modern studies on Cannabis, his “Eureka moments” being the identification of ∆9-tetrahydrocannabinol (∆9-THC, 1a) as the intoxicating agent of the plant, and the discovery of endocannabinoids, their endogenous analogues. On the other hand, sudden scientific revolutions are rare, and most advancements are the result of incremental developments, whose fil rouge through the history of knowledge deserves to be followed since both intellectually stimulating and predictive of future developments in the area. Cannabis (Cannabis sativa L.) is a remarkable example of a socially
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