# Biosynthesis of Nature-Inspired Unnatural Cannabinoidss
## 1 _Cannabis sativa_ and Cannabinoidss--An Introduction
In the US, _Cannabis_ is legally classified into hem, or fiber-type (less than 0.3% THC) and drug-type (more than 0.3% THC). Currently, cannabinoids for research and clinical use are mainly sourced from _C. sativa_ cultivar extracts. This method of production requires significant resources and is an unsustainable avenue for harvesting cannabinoids, given its recent rapid expansion in demand worldwide. _Cannabis_ farming requires extensive resources in order to cultivate these high-value plants in highly controlled environmental conditions. Research conducted by the Energy and Resources group in the Lawrence Berkeley National Laboratory in 2012 estimated that the cost of energy consumption from the indoor practice of _Cannabis_ cultivation in the US alone amounted to around USD 6 billion annually. In addition, the carbon dioxide gas emission from this practice to produce an average kilogram of the final product was equivalent to that of 3 million cars [16]. Additionally, _Cannabis_ farming contributes to the problem of illicit drug use due to the lure of recreational marijuana. According to a report by the American Civil Liberties Union, the US spent USD 3.6 billion annually in 2010 in _Cannabis_ law enforcement [17]. These complications fuel the need to find an alternative method of production that is cheaper, and more environmentally, economically and socially sustainable. Synthetic biology has provided the world with a solution in producing specific chemical compounds at a lower cost and higher selectivity using engineered microbes. The success of synthetic biology companies such as Amyris and Antheia in producing traditionally difficult and expensive medicine such as artemisinin for the treatment of malaria, and opioids for a variety of disease indications, have laid the foundations for many other biotech firms to follow. Several _Cannabis_-cultivating companies have shared up collaborations with synthetic biologists with the same goal in mind, producing specific cannabinoids without the use of _C. sativa_ cultivation. In recent years, several groups have published studies on the biosynthesis of cannabinoid precursors in micro-organisms such as bacteria and yeast strains [18; 19]. In 2019, a group led by [PERSON] published a landmark paper on the total biosynthesis of the cannabinoids, THCA and CBDA, using simple sugars in yeast [20]. The establishment of the cannabinoids biosynthetic pathway in heterologous systems has created new opportunities for producing rare cannabinoids such as cannabinoid (CBN) and cannabicyclol (CBL) for research into their therapeutic potential. Additionally, this has also accelerated the channel of uncovering novel cannabinoid-like analogues derivatized from these primary structures by reviewing the available chemical space. Cannabinoid analogues such as the ones produced by [PERSON] et al. with different side chains could elicit novel responses in the human body and uncover unique therapeutic applications. This review aims to summarize the recent advances in the field of synthetic cannabinoid biology and subsequently examine further strategies for creating novel cannabinoids. Lastly, understanding how classical phytocannabinoids interact with downstream signaling targets such as CB1 and CB2 will inform upstream diversification efforts.