**1. Introduction**

*Cannabis sativa* L. is a dioecious plant of the Cannabaceae family and is perhaps most famous for its production of the psychedelic metabolite delta-9 tetrahydrocannabinol (D9-THC). Cannabis has been used in traditional medicine for millennia across several continents; cannabis has been used in traditional Chinese medicine therapies for the treatment of gout, pain, convulsions, insomnia, cough, headache, itching, and anemia [1], while in traditional Aryuvedic practices, cannabis has been reported to stimulate digestion, function as an analgesic and sedative, and have aphrodisiac, anti-parasitic, and anti-viral properties [2]. Review articles covering the chemistry, pharmacology, botany, genomics, and ethnology of cannabis are regularly published as the plant's usage grows in prevalence [3–7]. In addition to THC, cannabis produces a number of other cannabinoid compounds with potent activities. Cannabidiol (CBD) is one non-psychedelic cannabinoid that has emerged as a popular botanical supplement ingredient [8]. A majority of Americans are aware of CBD, and ca. 18% have tried or are regular users of CBD products [9]. The US hempderived market in cannabidiol (CBD) topped \$4.7 billion in 2021 and is expected to reach \$12.0 billion by 2026 [10]. However, while many bioactivities can be ascribed to the presence of cannabinoids, cannabis is a prolific biosynthetic organism, producing over 750 known phytochemicals, including flavonoids and terpenoids, many of which possess putative medicinal properties [11], ye<sup>t</sup> the majority of these phytochemical constituents and their mechanisms of action have not been fully explored.

Terpenes (also termed isoprenoids) are the most diverse class of natural products and are the most abundant by mass [12]; in cannabis, terpenes account for 3–5% of the dry mass of the inflorescence [13]. Terpenes have incredible potential for bioactivity against both

infectious and chronic health conditions [14–16] and have been employed for thousands of years for therapeutic purposes, including in anti-inflammatory, anti-microbial, antioxidant, antitumor, and antidiabetic capacities [17]. In addition, terpenes often provide the foundation for the flavor and aroma of numerous plants and food products [18–20], including cannabis [21], granting the plant earthy or herbal aromas that combine with hints of sweet, citrusy, or piney scents. The terpene profile and content of cannabis has been reviewed previously [13,22,23]; however, analytical profiling studies, as well as cannabis phytochemistry reviews, traditionally focus on the more prevalent, terpenes such as myrcene, α-pinene, limonene, β-caryophyllene, linalool, humulene, ocimene, bisabolol, and terpinolene. The presence of a vast array of terpenes highlights the additional complexity of cannabis, as well as the further potential for bioactivity within this complex plant.

In botanical samples, mixtures of phytochemicals are often more effective than their individual constituents in isolation due to additive or synergistic interactions among compounds. Indeed, many chronic and infectious diseases are not regulated by a single cellular target, but often have multiple regulating pathways [24,25]. As organisms in a complex and dynamic ecological environment, plants have evolved to address this multifactorial disease etiology through the synthesis of structurally and functionally diverse phytochemicals. Thus, cannabis may also exert its bioactive effects via a combination of multiple constituents. Originally hypothesized in the late 20th century and termed the "entourage effect" [26], synergy between different cannabinoids has been documented in several studies. However, the potential for synergy between cannabinoids and other chemical classes, especially terpenes, has remained underreported.

This review aims to synthesize recent studies and information regarding the compositional diversity of terpenes, especially 'minor' terpenoid structures (compounds that are less prevalent in the plant on a by-mass basis) that have not been the focus of other reviews, ye<sup>t</sup> are found in diverse cultivars of cannabis and have unique and varied bioactivities as well. This is a unique feature of this review. In addition, we will build on the body of knowledge regarding how terpenes can potentially work in concert with cannabinoids to enhance bioactivity, as this is a timely topic given the upswing in interest in cannabis and potential synergy/entourage effects.
