The biosynthesis of the cannabinoids

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Abstract

Cannabis has been integral to Eurasian civilization for millennia, but a century of prohibition has limited investigation. With spreading legalization, science is pivoting to study the pharmacopeia of the cannabinoids, and a thorough understanding of their biosynthesis is required to engineer strains with specific cannabinoid profiles. This review surveys the biosynthesis and biochemistry of cannabinoids. The pathways and the enzymes’ mechanisms of action are discussed as is the non-enzymatic decarboxylation of the cannabinoic acids. There are still many gaps in our knowledge about the biosynthesis of the cannabinoids, especially for the minor components, and this review highlights the tools and approaches that will be applied to generate an improved understanding and consequent access to these potentially biomedically-relevant materials.

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The online version contains supplementary material available at 10.1186/s42238-021-00062-4.

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Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.

Ethan Russo (2011)

Tetrahydrocannabinol (THC) has been the primary focus of cannabis research since 1964, when Raphael Mechoulam isolated and synthesized it. More recently, the synergistic contributions of cannabidiol to cannabis pharmacology and analgesia have been scientifically demonstrated. Other phytocannabinoids, including tetrahydrocannabivarin, cannabigerol and cannabichromene, exert additional effects of therapeutic interest. Innovative conventional plant breeding has yielded cannabis chemotypes expressing high titres of each component for future study. This review will explore another echelon of phytotherapeutic agents, the cannabis terpenoids: limonene, myrcene, α-pinene, linalool, β-caryophyllene, caryophyllene oxide, nerolidol and phytol. Terpenoids share a precursor with phytocannabinoids, and are all flavour and fragrance components common to human diets that have been designated Generally Recognized as Safe by the US Food and Drug Administration and other regulatory agencies. Terpenoids are quite potent, and affect animal and even human behaviour when inhaled from ambient air at serum levels in the single digits ng·mL(-1) . They display unique therapeutic effects that may contribute meaningfully to the entourage effects of cannabis-based medicinal extracts. Particular focus will be placed on phytocannabinoid-terpenoid interactions that could produce synergy with respect to treatment of pain, inflammation, depression, anxiety, addiction, epilepsy, cancer, fungal and bacterial infections (including methicillin-resistant Staphylococcus aureus). Scientific evidence is presented for non-cannabinoid plant components as putative antidotes to intoxicating effects of THC that could increase its therapeutic index. Methods for investigating entourage effects in future experiments will be proposed. Phytocannabinoid-terpenoid synergy, if proven, increases the likelihood that an extensive pipeline of new therapeutic products is possible from this venerable plant. http://dx.doi.org/10.1111/bph.2011.163.issue-7. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish

Y GAONI, R Mechoulam (1964)

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The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.

R Pertwee (2008)

Cannabis sativa is the source of a unique set of compounds known collectively as plant cannabinoids or phytocannabinoids. This review focuses on the manner with which three of these compounds, (-)-trans-delta9-tetrahydrocannabinol (delta9-THC), (-)-cannabidiol (CBD) and (-)-trans-delta9-tetrahydrocannabivarin (delta9-THCV), interact with cannabinoid CB1 and CB2 receptors. Delta9-THC, the main psychotropic constituent of cannabis, is a CB1 and CB2 receptor partial agonist and in line with classical pharmacology, the responses it elicits appear to be strongly influenced both by the expression level and signalling efficiency of cannabinoid receptors and by ongoing endogenous cannabinoid release. CBD displays unexpectedly high potency as an antagonist of CB1/CB2 receptor agonists in CB1- and CB2-expressing cells or tissues, the manner with which it interacts with CB2 receptors providing a possible explanation for its ability to inhibit evoked immune cell migration. Delta9-THCV behaves as a potent CB2 receptor partial agonist in vitro. In contrast, it antagonizes cannabinoid receptor agonists in CB1-expressing tissues. This it does with relatively high potency and in a manner that is both tissue and ligand dependent. Delta9-THCV also interacts with CB1 receptors when administered in vivo, behaving either as a CB1 antagonist or, at higher doses, as a CB1 receptor agonist. Brief mention is also made in this review, first of the production by delta9-THC of pharmacodynamic tolerance, second of current knowledge about the extent to which delta9-THC, CBD and delta9-THCV interact with pharmacological targets other than CB1 or CB2 receptors, and third of actual and potential therapeutic applications for each of these cannabinoids.

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Author and article information

Contributors

Simon Rondeau-Gagné: srondeau@uwindsor.ca

John F. Trant:

ORCID: http://orcid.org/0000-0002-4780-4968

jtrant@uwindsor.ca

Journal

Journal ID (nlm-ta): J Cannabis Res

Journal ID (iso-abbrev): J Cannabis Res

Title: Journal of Cannabis Research

Publisher: BioMed Central (London )

ISSN (Electronic): 2522-5782

Publication date (Electronic): 15 March 2021

Publication date PMC-release: 15 March 2021

Publication date Collection: 2021

Volume: 3

Electronic Location Identifier: 7

Affiliations

GRID grid.267455.7, ISNI 0000 0004 1936 9596, Department of Chemistry and Biochemistry, , University of Windsor, ; 401 Sunset Avenue, Windsor, Ontario N9B 3P4 Canada

Author information

John F. Trant http://orcid.org/0000-0002-4780-4968

Article

Publisher ID: 62

DOI: 10.1186/s42238-021-00062-4

PMC ID: 7962319

PubMed ID: 33722296

SO-VID: b6d28525-e3c3-45ae-a15d-e379242def31

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

History

Date received : 21 September 2020

Date accepted : 17 February 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/501100000038, Natural Sciences and Engineering Research Council of Canada;

Award ID: 2017-06611-SRG

Award ID: 2018-06338-JFT

Award Recipient : Simon Rondeau-Gagné John F. Trant

Funded by: FundRef http://dx.doi.org/10.13039/501100000142, Arthritis Society;

Award ID: 19-0451

Award Recipient : John F. Trant

Funded by: FundRef http://dx.doi.org/10.13039/501100004489, Mitacs;

Award ID: IT16195

Award Recipient : John F. Trant

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Keywords: cannabinoid biosynthesis,enzymatic transformation,c. sativa,decarboxylation,enzymatic mechanism

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Keywords: cannabinoid biosynthesis, enzymatic transformation, c. sativa, decarboxylation, enzymatic mechanism

The biosynthesis of the cannabinoids

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Most cited references 88

Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects.

Isolation, Structure, and Partial Synthesis of an Active Constituent of Hashish

The diverse CB1 and CB2 receptor pharmacology of three plant cannabinoids: delta9-tetrahydrocannabinol, cannabidiol and delta9-tetrahydrocannabivarin.

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