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The responses of Cannabis sativa to environmental stress: a balancing act

Publication: Botany
27 July 2023

Abstract

Cannabis sativa L. is one of the oldest cultivated crops, used for its fiber and medicinal properties. The cannabis plant synthesizes a myriad of secondary metabolites, but the most valuable products from a medical and commercial standpoint are cannabinoids. Despite significant advances in elucidating the biochemistry and genetics that govern cannabinoid accumulation, we still do not have conclusive evidence for the role of these secondary metabolites in the physiology of C. sativa. In line with known functions of other secondary metabolites, the protective functions of cannabinoids against temperature stress, poor micronutrient soil content, drought, ultraviolet B radiation, and as antimicrobial agents have been suggested, but are yet to be conclusively demonstrated. Recent research suggests that the environment has a major effect on cannabis growth and productivity, but the relationship between stress, cannabinoid accumulation, and plant health is complex. Here, we summarize the current insights on how abiotic and biotic stresses affect C. sativa biology. We also examine the available evidence to support the hypothesis for the protective function of cannabinoids against environmental stressors. Maintaining optimal growth and high cannabinoid synthesis is a balancing act, one that can only be achieved by better understanding of the effects of the environment on the cannabis plant.

Introduction

Cannabis sativa L. is an annual dioecious herb native to Central and South Asia, and considered one of the oldest domesticated plants. Genomic evidence suggests that cannabis has already been domesticated by Early Neolithic times (12 000 B.P.; Ren et al. 2021), and the earliest archaeological evidence for its use as a fiber source dates back to ca. 8000 BC (McPartland et al. 2019). Since then, it has been widely used for building material, fuel, and medicine (reviewed in Romero et al. 2020). Despite its prevalent use throughout much of the recorded human history, global bans on cannabis as an illicit drug during the 20th century halted production and placed major roadblocks on basic research. Since its recent legalization in some countries, there has been a dramatic surge in scientific, agricultural, and medicinal interest in C. sativa. This interest has been largely driven by the therapeutic sector, since cannabis has many applications for the treatment of pain, epilepsy, schizophrenia, Alzheimer’s disease, and Parkinson’s disease (among others). In addition, cannabis is valuable as a source of fiber, and has also been recognized as a sustainable crop for food and biofuel production (Andre et al. 2016; Schilling et al. 2021). Realizing the true potential of the plant can only be achieved through a greater understanding of its biology.
The cannabis plant synthesizes a myriad of secondary metabolites, but the most valuable products from a medical and commercial standpoint are phytocannabinoids (Radwan et al. 2009; Fischedick et al. 2010). The most abundant cannabinoids in fresh plant material are Δ9-tetrahydrocannabinolic acid (THCA), cannabidiolic acid (CBDA), and cannabichromenic acid (CBCA). When decarboxylated by high temperatures, these compounds gain psychoactive properties (Flores-Sanchez and Verpoorte 2008). The accumulation of cannabinoids is dependent on the plant age and tissue type: the highest concentrations are found in the glandular trichomes of the female flowers and small leaves clustered within the inflorescence (Kim and Mahlberg 1997). Significant effort has been dedicated in breeding C. sativa varieties with traits beneficial for agricultural production, including higher cannabinoid yields (Clarke and Merlin 2016).
The optimal conditions for the cultivation of C. sativa have been studied extensively and are described in detail elsewhere (Chandra et al. 2017), and it is clear that every developmental stage is influenced by the growth environment. Modern-day cannabis cultivation has focused largely on optimizing the conditions in indoor controlled growth environments (i.e., greenhouses). Typically, controlled environments provide the plant with supplemental lighting with a defined intensity and spectrum, air filtration and air flow around the leaf surface to prevent microbial infections, heating and/or cooling to maintain optimal temperatures, and regulation of the humidity and CO2 concentration of the air (Chandra et al. 2017). Indoor-grown cannabis is susceptible to a number of microbe and insect pests, and appropriate disease mitigation approaches are required to avoid crop loss (Punja 2021). While indoor cultivation under tightly controlled conditions can increase yields, it has been classified as one of the most energy-intensive industries and is associated with very high operational costs (Warren 2015).
Growing cannabis outdoors is a viable option for large-scale cultivation. Growing plants outside provides fewer agronomic difficulties, but lower cannabinoid yields and different secondary metabolite profiles are reported when compared to cultivation in indoor controlled environments (Chandra et al. 2017; Zandkarimi et al. 2023). The culprits are unfavourable abiotic and biotic conditions that cause stress, the major yield-limiting factor for all crop plants. The environment must be finely balanced for optimal plant cultivation, since both deficiencies and excesses in various environmental factors can cause stress and substantially decrease plant growth, productivity, and survival. Understanding the effect of stress on plant physiology and development is a major goal in plant biology; however, cannabis has (perhaps not surprisingly) received much less attention compared to other major crop plants. This review pools published research on the effect of environmental stress on C. sativa and examines the known links between cannabinoid synthesis and cannabis stress responses.

Cannabis species, strains, cultivars, or chemovars?

Much of the available scientific insight on cannabis is complicated by the inconsistent classification of cannabis varieties. Both the species name (C. sativa) and the colloquial name (cannabis) are widely used in the scientific literature. In this manuscript, we will refer to C. sativa when indicating the plant species while the word “cannabis” will refer to the colloquial use of the plant. Cannabis sativa is the only member of the Cannabis genus, which is often divided into three subspecies with distinct phenotypic differences: ssp. sativa, ssp. indica, and ssp. ruderalis; however, this taxonomy has been questioned and extensive interbreeding has tangled any distinctions still further (Sawler et al. 2015; Lynch et al. 2016; McPartland 2018; Barcaccia et al. 2020).
Cannabis varieties are often described as “strains” conceptually equivalent to “cultivars” (McPartland and Small 2020), a term that has largely been appropriated by commercial and hobby breeders. For instance, the online database SeedFinder (https://en.seedfinder.eu) currently lists >29 000 distinct cannabis varieties, but these often reflect clandestine parentage. The genetic lineage of many of commercially used varieties is often unclear, does not always correspond to the advertized chemical profile and, in some cases, may originate from the black market. Unregulated domestication and hybridization of cannabis varieties has even been associated loss of chemical diversity in the modern cannabis landscape (Mudge et al. 2018). Thus, a given strain name may not reflect its actual genetic background or chemical profile (Hazekamp and Fischedick 2012; Pusiak et al. 2021; Smith et al. 2022). Defining the usage of the term “strain” has been proposed (Pollio 2016), but this nomenclature has not been standardized yet.
Agricultural and plant sciences define plant cultivars as varieties developed over long periods of breeding and selection for desirable traits. Agricultural cultivars are internationally accredited and have well-defined phenotypic and chemical characteristics, which can be consistently reproduced either asexually through cloning or sexually through seed production. For legislative purposes of C. sativa production, the most important classification is that of drug-type (marijuana) with >0.3% THC and fiber-type (hemp) with <0.3% THC on basis of dry plant tissue. Commercial hemp cultivars have already been accredited (e.g., 84 approved cultivars for the 2022 Growing Season in Canada; Government of Canada 2023), but accreditation has not been achieved for drug-type C. sativa with higher THC levels.
More recently, the term chemovar/chemotype has been applied to cannabis varieties based on cannabinoid levels and profiles: (1) type I (THCA/CBDA >> 1), type II (CBDA/THCA ≈ 1), type III (THCA/CBDA << 1), type IV (cannabigerol (CBGA)-dominant, with very low THC + CBD content), and type V (very low cannabinoid content overall). Types I and II are considered as medical (or drug-type) cannabis, while chemotypes III–V are described as hemp (Hillig and Mahlberg 2004; Pacifico et al. 2006; Schilling et al. 2021). It must be noted that classification based on cannabinoid levels is somewhat misleading. The C. sativa plant is very phenotypically diverse in traits other than cannabinoid levels, including height, leaf shape, photoperiod, and highly variable responses to environmental stimuli (discussed in more detail below). Furthermore, chemotypes do not necessarily constitute a phylogenetic classification based on evolutionary relationship. The dioecy of the plant leads to high levels of heterozygosity even within a single cannabis variety (Clarke and Merlin 2016; Schilling et al. 2021) and, unlike previously assumed, many morphological traits (e.g., leaf shape) do not correlate with phytochemistry (Vergara et al. 2021). Many traits important for plant growth, development, and stress resilience have not been examined in detail.
To summarize, the vast amount of C. sativa variants coupled with a lack of defined genetic pedigrees poses a question as to the comparability of studies looking at different lineages. For instance, the literature surveyed here involved no less than 52 different hemp and 35 different medical cannabis varieties, inconsistently defined as cultivars, strains, or chemovars. When directly compared, many varieties display different responses to the same stressor, hinting to vastly different genetics within the species. For consistency, in this manuscript we use the terms “variety, cultivar, strain, and chemovar” interchangeably and as they appear in the original cited work. In addition to clearly defining the nomenclature, it may be relevant to consider utilizing a smaller number of standardized and genetically stable varieties in the future to ensure verifiable results that can be systematically applied to larger growth operations.

Regulation of cannabinoid synthesis: the story so far

Plant secondary metabolites are compounds that are not essential for plant growth and development but are produced to make the plant more competitive in its environment. First isolated from C. sativa, phytocannabinoids are a group of more than 90 terphenophenolic secondary metabolites with bioactive properties. Related compounds have been detected in a few other flowering plants (Rhododendron sp., Helichrysum sp.), liverworts (Radula sp.), and fungi (Albatrellus, Cylindorocarpon) but none are commercially used (Gülck and Møller 2020). Major secondary metabolite groups, such as phenolics, flavonoids, alkaloids, and terpenes, have demonstrated roles as regulators of defenses against pathogens and herbivores, facilitators or micronutrient uptake, and regulators of growth under abiotic stress (Kroymann 2011; Erb and Kliebenstein 2020; Pang et al. 2021). In line with the known functions of other secondary metabolites, protective functions of cannabinoids against temperature stress, poor micronutrient soil content, drought, UV-B radiation, and as antimicrobial agents have been suggested, but are yet to be conclusively demonstrated. We discuss this in more detail below.
The biochemical pathway for cannabinoid synthesis was recently elucidated, and many of the genes in this pathway have been characterized in detail (Luo et al. 2019; van Velzen and Schranz 2021; Innes and Vergara 2023). The three main cannabinoids from C. sativa (THCA, CBDA, and CBCA) are structurally similar and produced from the same precursor molecule, CBGA. This reaction is catalyzed by the flavoproteins Δ9-tetrahydrocannabinolic acid synthase (THCAS) and cannabidiolic acid synthase (CBDAS), encoded by multiple genes with a very high sequence similarity (96% at the nucleotide level). Furthermore, these enzymes are also promiscuous, and can synthesize multiple cannabinoids (including exotic, uncharacterized species) from the same precursor simultaneously (Zirpel et al. 2018). The conversion of CBGA to THCA/CBDA is dependent on a covalently bound flavin adenine dinucleotide, requires molecular oxygen, and releases equimolar amounts of hydrogen peroxide (H2O2) alongside the product (Sirikantaramas et al. 2004; Taura et al. 2007; Shoyama et al. 2012). It has been demonstrated that cannabinoid amounts and profiles are developmentally regulated and largely reflected in the genetics that underpin this biosynthetic pathway (Barcaccia et al. 2020; Kovalchuk et al. 2020; Hurgobin et al. 2021). Increased expression of THCAS/CBDAS and accumulation of cannabinoids coincide with flower maturation and glandular trichome development (Liu et al. 2021; Apicella et al. 2022).
Our insights on whether the expression of these genes responds to environmental cues are still in infancy. Recent work detected upregulation of THCAS and CBDAS by treatment with salicylic acid (SA), γ-aminobutyric acid (GABA) (Jalali et al. 2019), and ascorbic acid (Soltan and Dadkhah 2022), compounds with known roles in plant stress signalling. An increase in the accumulation of cannabinoids in leaves and flowers, albeit without an accompanying upregulation in gene expression of THCAS/CBDAS, was also observed when plants were treated with methyl jasmonate and SA (Apicella et al. 2022; Garrido et al. 2022). This suggests that cannabinoid accumulation may be triggered by plant stress response elicitors, but more work is needed to conclusively show that the expression of genes encoding key enzymes in the cannabinoid synthesis pathway are environmentally regulated.

High cannabinoid accumulation may be damaging to plant tissues

The final step in the cannabinoid synthesis pathway occurs in the apoplastic cavity of the stalked glandular trichomes (Sirikantaramas et al. 2004; Marks et al. 2009). The highest density of trichomes, and consequently the highest cannabinoid content, is found on the inflorescences of female flowers (Tanney et al. 2021). Cannabinoids are also synthesized in vegetative tissues throughout the life cycle in both male and female plants, albeit at lower concentrations (Pacifico et al. 2008; Stack et al. 2021). Trichomes form a secretory cavity bordered by the plant cuticle and secretory disc cells, which effectively isolate the produced cannabinoids from the somatic plant cells (Livingston et al. 2020). Modern cannabis breeding has focused on selecting plants with high trichome densities and cannabinoid content as superior traits for commercial THC/CBD production (Clarke and Merlin 2016); however, it is not known whether selecting for these traits is beneficial to the plant in an ecological or evolutionary context. For instance, many secondary metabolites from other plant species, such as the diterpene sclareol accumulated by Nicotiana ssp., can be toxic to plant cells. Thus, these compounds are often sequestered in glandular trichomes, the apoplast, or in vacuoles to prevent tissue damage (Sirikantaramas et al. 2008; Shitan 2016). Cannabinoids may be one such compound class.
There are several lines of evidence that suggest that cannabinoids may be harmful to plant cells. Application of THCA and CBCA to plant leaves, either directly or by exfoliating the leaf cuticle, resulted in significant chlorophyll loss and cell death in the affected tissue. Similarly, direct treatment of C. sativa suspension cells with THCA and CBCA induced rapid cell death accompanied by chlorophyll and deoxyribonucleic acid (DNA) degradation (Morimoto et al. 2007). THCA-induced cell death was also demonstrated in tobacco, rice, soybean, Arabidopsis thaliana, and Scutellaria baicalensis, all of which lack cannabinoid-producing abilities (Morimoto et al. 2007; Shoyama et al. 2008). The necrosis-inducing effect was absent when suspension cells were treated with olivetolic acid and geraniol, two direct precursors of CBGA that lack the cannabinoid skeleton, suggesting that it is the particular cannabinoid chemical structure that contributes to cellular damage (Shoyama et al. 2008). It has been shown that cell death was triggered by opening of the mitochondrial permeability transition (MPT) pore, resulting in loss of mitochondrial membrane potential, mitochondrial swelling, and ultimately mitochondrial dysfunction. These studies hypothesized that THCA, CBCA, and CBGA affect mitochondrial function directly by mediating opening of the MPT pores (Morimoto et al. 2007). Mitochondria are key players in executing necrotic and programmed cell death in plants (Reape et al. 2008). The implications of this finding are currently not known, but it may be possible that cannabinoids are involved in processes that rely on controlled induction of cell death, including senescence or the hypersensitive response that limits the spread of pathogens (Reape and McCabe 2008).
Plant growth, biomass, and yield are directly proportional to the photosynthetic performance of the plant, which in turn depends on the overall health of the leaf mesophyll tissue (Demura and Ye 2010). A strong negative correlation between THCA accumulation and photosynthetic performance in several C. sativa accessions was recently reported (Khajuria et al. 2020). High-THCA strains exhibited the shortest height, less branching, and lesser total biomass compared to strains with lower THCA levels. Reduced growth was accompanied by decreased photochemical efficiency at the level of the light harvesting complexes and significant degradation of photosynthetic assemblies in leaf tissue. Furthermore, high-THCA strains had high levels of lipid peroxidation within the leaf tissues, suggesting membrane damage by reactive oxygen species (ROS; Khajuria et al. 2020). ROS production is regarded as normal by-products of chloroplast and mitochondrial metabolism in plants but can be highly damaging when present in amounts that exceed the antioxidant capacity of the cell (Dumanović et al. 2021). The underlying causes behind the inverse correlation between photochemical efficiencies and THCA content is not currently known. It must be noted that the enzymatic reaction that leads to cannabinoid biosynthesis is accompanied by accumulation of H2O2, ROS with known roles in necrotic and apoptotic cell death in plants (Smirnoff and Arnaud 2019). Whether the decreased plant growth is due to excessive ROS accumulation during THCA biosynthesis, mitochondrial dysfunction due to MPT, or a yet undescribed mechanism is not yet known but warrants future investigation.

The effects of environmental stress in plant health

Stress refers to the biotic or abiotic conditions that adversely affect growth, development, and productivity and is often an unavoidable occurrence in outdoor agriculture. Abiotic stress is caused by deficiencies or excesses in environmental factors such as light, temperature, water availability, and the presence of inorganic compounds. Biotic stress stems from living organisms and includes herbivore damage, microbial diseases, and plant-to-plant overcrowding. Plants have many ways to respond to stress, ranging from changes in gene expression, physiology, organ and tissue architecture, and modifications in primary and secondary metabolism. The complexity of this response is heavily influenced by the duration and intensity of the stress, the simultaneous occurrence of multiple stressors, the plant genotype and developmental stage at which the stress is applied (Cramer et al. 2011; Suzuki et al. 2014; He et al. 2018; Zhang et al. 2020; Iqbal et al. 2021). One of the first external symptoms of stress is decreased growth. While this can be a passive consequence due to a lack of a key resource, plants under stress can also actively induce responses that prevent stress and repair cellular damage at the expense of growth. It has been widely recognized that a balance must be achieved between inducing stress responses and maintaining sufficient growth and productivity. How plants achieve such balance is not only a fundamental scientific question, but also of vital importance for agriculture.
While the genetic and morphological underpinning of cannabinoid accumulation have been well studied (Schilling et al. 2021), the role and function of cannabinoids in the physiology of the plant itself is yet to be determined. Approximately 30% of all vascular plant species have glandular trichomes to secrete and store secondary metabolites, including flavonoids, monoterpenes, or sesquiterpene lactones (Huchelmann et al. 2017). The contribution to many of these compounds in defense against diverse abiotic and biotic environmental challenges have been clearly shown and are reviewed in detail elsewhere (Peiffer et al. 2009; Agati et al. 2012; Schuurink and Tissier 2020). Cannabinoids could play a similar role in the C. sativa plant; however, relatively little work has been performed in defining the role of cannabinoids during environmental stress. In this review, we summarize the main findings on the role of environmental stress in C. sativa growth and secondary metabolite accumulation (Table 1).
Table 1.
Table 1. A summary of current insights on the role of environmental stressors on cannabinoid accumulation in Cannabis sativa.

UV and high light stress

Light is one of the most important environmental parameters that impact plant physiology. Light is both a source of energy utilized through photosynthesis and an important developmental signal. Light is required for plant function, but exposure to insufficient or excess light levels can have detrimental effects. Whereas exposure to insufficient light limits photosynthetic activity, exposure to high light levels that exceeds the energetic demands of photosynthesis can cause oxidative stress, photodamage, and photoinhibition. Prolongation of the light period, recurrent periods of light intensity fluctuations, as well as excessive exposure to ultraviolet light can also lead to plant stress (Roeber et al. 2021 and references therein).
As a species, C. sativa has a remarkable ability to tolerate high light intensities. In a series of experiments examining the interplay of light intensity, temperature, and air CO2 concentration, Chandra et al. (2008) showed that a high-potency Mexican C. sativa variety achieves maximum rate of photosynthesis at light intensities as high as 2000 µmol m−2 s−1, but only if the growth temperature is kept at an optimal 25 °C (Chandra et al. 2008). Similarly, several different drug-type and fiber-type varieties grown at 1500 µmol m2 s−1 exhibited decreased photosynthetic rates only at unfavourable temperatures >30 °C (Chandra et al. 2011). Significantly, these studies did not discern a saturating point for these responses up to the highest tested light intensity of 1500 µmol m−2 s−1, nor any other symptoms of photoinhibition. Recent work, however, has suggested that photosynthetic yields at high light intensities can be maintained only in young leaves. In contrast, in older leaves within the canopy photosynthetic rates were saturated at <500 µmol m−2 s−1 (Bauerle et al. 2020). These studies emphasize the exceptional ability of cannabis to convert photosynthetic energy into yield; however, its capacity to utilize light as an energy source is affected by age and other environmental conditions.
No clear link has been established between the ability of C. sativa to thrive in high light and protective functions of the accumulated cannabinoids. Linear increases in cannabinoid yield and inflorescence densities were observed with increasing light intensities, but this was not accompanied with appearance of light stress symptoms (Vanhove et al. 2011; Potter and Duncombe 2012; Eaves et al. 2020; Rodriguez-Morrison et al. 2021a). Chandra et al. (2015) examined the light responses of four varieties with varying THC levels grown at light intensities up to 2000 µmol m−2 s−1, but the authors did not detect a clear correlation between photosynthetic efficiencies, light stress symptoms, and THC levels. Thus, it is likely that high cannabinoid accumulation is a result of an efficient light harvesting and carbon fixation processes, rather than a protective response to high light stress. The specific mechanisms that contribute to light stress resilience have not been examined but would be a fruitful avenue for future work.
It has been speculated that the accumulation of cannabinoids protects the female C. sativa plant from UV light-induced damage. In nature, plants are exposed to a small but significant fraction of UV radiation (100–400 nm) relative to the amount of photosynthetically active radiation (400–700 nm). Naturally occurring UV light is a signal that affects many plant processes, including flowering time, interactions with plant pollinators, plant morphology, and secondary metabolite accumulation in many plant species (Hideg et al. 2013; Tossi et al. 2019; Meyer et al. 2021). On the other hand, UV light (especially at increased intensities) can cause protein and DNA damage, culminating in necrotic cell death (Czégény et al. 2016; Tossi et al. 2019).
Early work on field-grown C. sativa found higher THCA levels in plants grown in high-altitude regions that typically receive higher solar UV radiation (Small and Beckstead 1973; Pate 1983). Early controlled-environment studies have also suggested that UV exposure induces THCA accumulation (Fairbairn and Liebmann 1974; Lydon et al. 1987), proposing an ecologically relevant role of this secondary metabolite for protection of the female reproductive tissues. More recent studies, however, have challenged this conclusion. A very short 10 min treatment with UV-C light did not induce a significant change in cannabinoid content (Marti et al. 2014). In a study that mimicked natural UV exposures, a 60 day UV light treatment of two modern C. sativa varieties with a balanced THCA/CBDA ratio was found to decrease inflorescence size and cannabinoid yields. This treatment also induced a range of negative effects on plant growth and development, including smaller leaves and decreased biomass (Rodriguez-Morrison et al. 2021b). This work does not exclude the possibility that shorter exposures during the flowering stage may increase cannabinoid levels, but these strategies warrant further examination and may provide more insights on the protective roles of cannabinoids during plant reproduction.

Temperature stress

Plant growth is strongly affected by temperature with species-specific temperature range for optimal growth, and minimum and maximum boundaries for survival (Hatfield and Prueger 2015). In general, temperate plant species undergo heat stress at >37 °C, chilling stress in a range from 0 °C to 15 °C, and freezing stress at <0 °C. Plants respond to temperature stress systemically and alter many molecular processes including protein synthesis and activity, accumulation of antioxidants and compatible solutes, downregulation of primary metabolism, and alteration in membrane lipid composition. Physiologically, temperature stress results in decreased germination rates, low photosynthetic rates, decreased growth, and low seed production (reviewed in Allakhverdiev et al. 2008; Hasanuzzaman et al. 2013; Guo et al. 2018).
Only a handful of studies have examined the effects of heat stress on C. sativa physiology. Chandra et al. (2011) examined the growth and photosynthetic performance of three drug-type and four fiber-type C. sativa varieties under temperatures ranging from 20 °C to 40 °C. Optimal temperatures for growth and photosynthesis were strain-specific and ranged from 25 °C for strains originating from temperate regions (e.g., W1 from Switzerland) to 35 °C for strains adapted to warmer regions (e.g., HPM from Mexico). Photosynthetic rates in all varieties were negatively affected above their respective optimum, due to decreased water use efficiency and transpiration water loss (Chandra et al. 2011). Similarly, two fiber-type C. sativa strains exhibited decreased photosynthetic performance during the hottest days of the summer, an effect that was exacerbated by high light intensities (Herppich et al. 2020).
Responses to chilling and freezing stress appear to be equally strain dependent. Working with nine fiber-type strains, Mayer et al. (2015) demonstrated that plants exposed to a short-term chilling stress exhibit an improved tolerance to a subsequent longer or more severe cold stress. These responses are strain-specific and some varieties (e.g., Finola and Yvonne) exhibit a high capacity to cold acclimate and survive short-term freezing (1 h), while others (e.g., Alyssa and CRS-1) are cold sensitive and have lower survival rates in response to an equivalent stressor (Mayer et al. 2015). Cold-acclimation efficiency was highly correlated with increased expression of cold-regulated (COR) genes regulated by DNA methylation and chromatin modifications (Mayer et al. 2015).
While these results provide the first links between C. sativa genotypes and the resilience to thermal stress, there is a paucity of evidence correlating stress responses with cannabinoid accumulation. Field studies have suggested that plants grown at cooler temperatures (23 °C/16 °C) produce more THCA and CBDA than plants grown at higher temperatures (32 °C/23 °C) (Bazzaz et al. 1975; Murari et al. 1983), although there is currently no experimental evidence using controlled conditions to substantiate these early results. None of the studies described above revealed a response that could be linked to THCA/CBDA accumulation. In all cases, variations between strains were largely related to the geographical region of origin rather than the secondary metabolite profile of the strain. Furthermore, a 7 day heat stress (45–50 °C) in the first 2 weeks of flowering in a high-CBD hemp variety leads to a significant decrease in the production of CBGA and a nonsignificant reduction in the levels of CBDA and THCA (Park et al. 2022). Similar studies are currently lacking for high THCA-producing C. sativa. Temperature stress can affect the secondary metabolite profile in other plant species (reviewed in Li et al. 2020), but experimental evidence for a similar effect on cannabinoids is currently lacking.

Water stress

Water availability plays a central role in plant physiology. Drought stress results from limited water availability, and is characterized by reduced leaf turgor pressure, stomatal closure, suppressed photosynthetic processes, and decreased activity of primary metabolism (Farooq et al. 2009; Seleiman et al. 2021). Waterlogging and flooding stress is triggered by partial or full submergence of the plant under water. This can deprive the plant tissues of O2, leading to hypoxia or anoxia. Waterlogged plants also experience a secondary stress due to rapid tissue reoxygenation when the flooding subsides (Perata et al. 2011; Fukao et al. 2019). Both drought and flooding can be highly damaging to plants.
All studies that have examined the resilience of C. sativa to drought have been performed on hemp varieties with low or moderate CBDA accumulation. Cannabis sativa is moderately resilient to drought in field trials and is known as a resource-use efficient crop (Tang et al. 2018). Short-term exposure of C. sativa to limited water availability leads to increase in water use efficiency due to stomatal closure; however, if drought stress is prolonged (up to 15 days) the leaves begin to senesce (Tang et al. 2018). This is consistent with typical responses to drought stress in other plant species (Tardieu et al. 2018). Different hemp strains have been shown to utilize different strategies to adapt to drought stress during field trials in a dry and hot summer season. For example, the multipurpose hemp strain Ivory employed an “optimistic” strategy with early and high CO2 assimilation gains, but at the expense of early senescence and shorter growth season. In contrast, the hemp strain Santhica 27 decreased photosynthetic rates due to stomatal closures and employed a “slow and steady” strategy of decreased growth, but with ultimately higher yields (Herppich et al. 2020). It should be noted, that while hemp is considered a species that is tolerant to drought, the final yield parameters including biomass, stem thickness, and fiber content are nevertheless decreased due to lack of water (Amaducci et al. 2008; Tang et al. 2018).
Experiments under controlled conditions revealed similar trends. Blandinières et al. (2021) evaluated the drought stress tolerance and transpiration efficiency in 26 commercial European hemp cultivars in the germination, seedling, and vegetative stage. While no clear trends were observed with regard to the geographical origin of these strains, it was suggested that cultivars characterized by early flowering phenotype are more resilient to drought, compared to those that have a longer growth season and late flowering phenotype (Blandinières et al. 2021). Molecular and physiological characterization of the basis of drought tolerance in hemp is still in infancy. Treatment with exogenous gibberellins (GA) significantly improved the germination rate of two drought-sensitive hemp cultivars (Yunma and Bamahouma) under osmotic stress. GA application significantly increased the accumulation of soluble sugars, proteins, and antioxidants, revealing that the mechanisms of drought control are under hormonal control (Du et al. 2022). These results were corroborated by genome-wide expression profiling of the drought-sensitive Yunma cultivar, revealing an involvement of abscisic acid and auxin biosynthesis pathways in drought stress responses (Gao et al. 2018).
There is evidence that drought stress affects the accumulation of cannabinoids, although whether this response has a protective function is not known. Early research demonstrated that plants grown in hotter, drier environments had increased trichome densities (Sharma 1975). Recent work positively correlated drought stress tolerance with CBD accumulation in hemp in both field and controlled-environment experiments (Sheldon et al. 2021). In addition, highly controlled and moderate drought stress during the flowering stage was found to increase the concentration in both THCA and CBDA (12% and 13%, respectively) without a decrease in plant health and inflorescence weight in the high-CBD strain NC:Med (Caplan et al. 2019). While promising, these results appear to be strain-specific. A 7 day application of drought during the first 2 weeks of flowering in the hemp variety Green-Thunder led to 40% increase in CBG but a 70%–80% decrease in CBD and THC (Park et al. 2022). Waterlogging stress has not been examined in detail, but 3 weeks of moderate waterlogging during the flowering stage revealed no significant alterations in cannabinoid levels or profiles in three high-CBD hemp varieties (Toth et al. 2021). Whether these insights can be extended to high-THC strains remains to be determined.

Nitrogen, phosphorus, and potassium deficiency and toxicity

Nutrient stress is defined as either the excess or deficiency of mineral elements indispensable to plant growth. The uptake, transport, and distribution of inorganic nutrients have been extensively studied (Yang et al. 2018; Pandey et al. 2021; Kumari et al. 2022). The symptoms of nutrient deficiency and toxicity depend on the element but typically include chlorosis, inhibition of photosynthesis, stunted growth of vegetative and reproductive tissues, and necrosis. Optimal nutrient levels depend on the plant species and age, but are also influenced by environmental variables such as water availability, soil type, temperature, and the presence of microbial symbionts (Kumari et al. 2022). The macronutrients that have received the most attention are nitrogen (N), phosphorus (P), and potassium (K), since they are of vital importance in many metabolic processes, including secondary metabolism in numerous plant species (Mosa et al. 2022). Due to agronomic importance, optimal mineral nutrition and plant fertilization have received significant attention in C. sativa (reviewed in Malík et al. 2021). Many studies have detected a correlation between increased nutrient availability and cannabinoids, likely stemming from improved plant health overall (Haney and Kutscheid 1973; Coffman and Gentner 1975; Latta and Eaton 1975; Bolt et al. 2021; Kakabouki et al. 2021; Yep and Zheng 2021).
The optimal range for nitrogen supply for cannabis growth depends on the cannabis strain and the method of cultivation. Thus, what constitutes nitrogen stress is not easy to define. For instance, optimal soil concentrations of nitrogen for field-grown hemp have been reported in the range of 100–400 mg/L, but these recommendations differ for indoors or hydroponically grown plants, depend on the strain, and have to take other environmental conditions into account (Vera et al. 2004; Aubin et al. 2015; Malík et al. 2021). Optimal nitrogen levels in high-THC medical cannabis were reported as 160 mg/L, and cultivation with lower nitrogen levels (<80 mg/L) was found to correlate with decreased photosynthetic capacity, chlorosis, increased lipid peroxidation, and growth retardation of root, inflorescence, and leaf tissue (Saloner and Bernstein 2020, 2021; Zhu et al. 2022). Studies performed on field-grown, fiber-rich hemp have suggested that this species is able to maintain high photosynthetic capacities when grown at low nitrogen fertilization, thus suggesting an excellent potential as a sustainable bioenergy crop compared to traditionally cultivated species such as cotton and kenaf (Tang et al. 2017). The level where excessive nitrogen fertilization results in toxicity has been reported as >160 mg/mL, resulting in decreased biomass and yields (Saloner and Bernstein 2021).
Phosphorus deficiency (but not toxicity) stress has also been defined. High-THC cannabis strains have a wide optimal range for phosphorus fertilization, with a recommended application of 30 mg/L in the vegetative stage. Lower concentrations lead to decreased dry weight, lower chlorophyll concentrations, decreased photosynthetic rates, and decreased uptake of other mineral nutrients (Shiponi and Bernstein 2021a, 2021b). The upper limit for phosphorus toxicity is not currently known, but it must be noted that increased fertilization in the range of 30–90 mg/L did not result in improved growth (Shiponi and Bernstein 2021a, 2021b).
High-THC and high-CBD strains of C. sativa have been shown to suffer potassium deficiency at concentrations <60 mg/L, alongside severely stunted growth, decreased pigment accumulation, and lower photosynthetic performance (Saloner et al. 2019; Saloner and Bernstein 2022). The severity of the symptoms is strain specific. Severe potassium deficiency (0.2 mmol/L) leads to decreases in photosynthesis in both resilient and sensitive hemp strains; however, resilient strains can acclimate through increases in chlorophyll synthesis rates, increases in antioxidant defenses, and stress hormone biosynthesis pathways (Cheng et al. 2021). These studies bring some of the first insights that may inform on strain selection for optimal potassium fertilization.
Several studies have suggested that nutrient deficiencies may induce cannabinoid accumulation. Increased CBD, THC, and CBG levels were detected in plants fertilized with 50 ppm N, when compared to those fertilized with 150 ppm N (Anderson et al. 2021). Saloner and Bernstein (2021) found that cannabinoids were highest under N-deficit conditions (30 mg/L) and that both THCA and CBDA decreased significantly (69% and 63%, respectively) when N fertilization was increased. Growth with low K-fertilization (15 mg/L) resulted in highest levels of all cannabinoids, and significant deceases were observed when plants were grown with high K-content (Saloner and Bernstein 2022). Similarly, THCA and CBDA content was the highest under P-deficiency stress (<30 mg/L) and significantly decreased with increased nutrition (Shiponi and Bernstein 2021b). Enhanced NPK supplementation increased CBG levels (71%) but significantly decreased the levels of other cannabinoids (37%–39%) when compared to commercial NPK fertilizers (Bernstein et al. 2019). The ecological significance of these findings is not clear, but it is a promising venue for defining the appropriate nutrient balance to achieve both high biomass and cannabinoid content.

Salinity and heavy metal stress

Excessive salinity is a global ecological and agricultural issue, that impairs plant growth and development via osmotic and oxidative stress (Miller et al. 2010; Parihar et al. 2015; Tardieu et al. 2018). As a species, C. sativa has moderate salinity resilience. Germination and seedling development in two commercially relevant hemp varieties (Yunma 5, Bamahouma) was moderately delayed at 100 mmol/L NaCl, and more severe stress symptoms and significant decreases in growth were demonstrated at 300 mmol/L NaCl (Hu et al. 2018, 2019). Transcriptome profiling in two different cannabis varieties revealed strain-specific adaptive mechanisms to acute salinity stress (500 mmol/L NaCl, up to 5 days). Bamahouma regulated gene expression rapidly (within 2 days of salinity treatment), suggesting an ability to respond and acclimate to salinity stress (Liu et al. 2016). A 100 mmol/L NaCl treatment in the hemp variant K94 induced alteration in the expression of genes involved in hormone biosynthesis and mitogen-activated protein kinase (MAPK) signalling pathways. In contrast, the hemp variant W20 altered the expression of genes associated with phenylpropanoid biosynthesis and plant hormone signal transduction pathways (Zhang et al. 2021a). Many of the responses of C. sativa to salinity stress are shared with other species, including differential regulation in genes associated with photosynthesis, light harvesting, carbon metabolism (Liu et al. 2016; Cao et al. 2021), phenylpropanoid biosynthesis, hormonal signalling (Cao et al. 2021; Zhang et al. 2021a), lignification, and rapid cell wall biosynthesis (Guerriero et al. 2017).
Current evidence suggests that salinity stress negatively affects cannabinoid accumulation. Exposure of two hydroponically grown drug-type C. sativa cultivars, Nordle and Sensei Star, to a very mild salinity stress (5 mmol/L) is sufficient to significantly decrease THCA yields without negatively affecting the growth (Yep et al. 2020). Whether the same is true for soil grown plants is yet to be determined.
The ability of fiber-type C. sativa to thrive on soils contaminated by heavy metals has been recognized, suggesting that this plant has very good prospects as a phytoremediator. The ability of C. sativa to uptake, translocate, and sequester toxic metals such as cadmium (Cd), nickel (Ni), lead (Pb), chromium (Cr), zinc (Zn), copper (Cu), and selenium (Se) has been reviewed in detail elsewhere (Wu et al. 2021; Placido and Lee 2022). Hemp can thrive in heavily contaminated sites such as landfills and mine areas, where very few crops could survive (Mihoc et al. 2012), but the mechanism behind the exceptional ability of C. sativa to tolerate heavy metal toxicity has not been fully elucidated. Growth on heavy metals may also impact the accumulation of cannabinoids. For instance, cultivation of six hemp cultivars on Ni-contaminated soil was associated with increased CBD content and CBDAS expression, when compared to plants grown without the presence of the contaminant. Significantly, Ni-exposed plants did not display lower growth rates, toxicity symptoms, or decreased biomass (Husain et al. 2019). Thus, C. sativa remains a strong candidate for a phytoremediation crop and may lead to sustainable production of medicinal compounds.

Biotic stress (pathogen, herbivores, and plants)

Biotic stress stems from the negative interactions of plants with other living organisms, resulting in irreversible cell and tissue damage. Biotic stress includes fungal, bacterial, and viral diseases (Wiesner-Hanks and Nelson 2016; Miller et al. 2017; Vannier et al. 2019), physical damage due to herbivores, insects, and nematodes (Lucas-Barbosa 2016; Erb and Reymond 2019; Hamann et al. 2021), and plant-to-plant overcrowding (Huber et al. 2021; Wang et al. 2021).
One of the greatest challenges facing cannabis producers is the recognition and eradication of pests and pathogens that, if not effectively managed, can affect entire monoculture crops. Plant pathogens can infect the roots, leaves, and inflorescences in C. sativa and thus, affect all growth stages of the plant. Most known diseases in C. sativa are the result of fungal and oomycete infections, including those caused by Botrytis cinerea (grey mold), Fusarium species and Pythium species (root and crown rot), Alternaria species (black mold), and Golovinomyces spp. (powdery mildew). These diseases can cause a number of symptoms including chlorosis, wilting, bud necrosis, and root rot (comprehensively reviewed in Punja 2021). While bacterial pathogens of C. sativa are less commonly reported (Punja 2021), viral and viroid diseases have been identified as a massive threat to cannabis cultivation worldwide. The Hop latent viroid (HLVd) is a protein-free, low molecular weight, plant pathogenic RNA molecule originally identified as a worldwide threat to the cultivation of hops (Humulus lupulus; Puchta et al. 1988), the closest C. sativa relative (Yang et al. 2013). With the widespread cultivation of C. sativa, HLVd has been detected in a significant percentage of indoor growth facilities (Adkar-Purushothama et al. 2023). HLVd causes the “duds” disease that significantly decreases inflorescence size, trichome density, and cannabinoid synthesis (Bektaş et al. 2019; Warren et al. 2019). Recent research has demonstrated the presence of a wide variety of virus and viroid sequences in C. sativa leaf samples (Chiginsky et al. 2021). Such studies will be critical for developing early disease detection strategies, and effective disease management.
Recent findings demonstrate that cannabinoids, alone or in combination with other secondary metabolites, have antimicrobial effects on human bacterial and fungal pathogens (Schofs et al. 2021). It is not currently known whether the same is true for plant pathogens. Increase in cannabinoid accumulation during exogenous treatment with the stress-related phytohormones SA and jasmonic acid (JA) induces accumulation of cannabinoids (Jalali et al. 2019; Garrido et al. 2022) but there is little evidence that pathogen infections are associated with similar increases. In fact, most reported diseases on C. sativa are accompanied by harvest loss due to poor plant growth and tissue damage (Punja 2021). Treatment with Golovinomyces spadiceus (powdery mildew) did not induce accumulation of cannabinoids when compared to nontreated plants (Toth et al. 2021).
When grown outdoors, C. sativa is threatened by a number of pests that forage above and below ground, including nematodes, spider mites, aphids, thrips, beetles, flies, and birds (McPartland et al. 2000). Pests feeding on leaves, flowers, and seeds are most easily observed and studied; root and stalk feeders remain poorly understood (reviewed in Cranshaw et al. 2019; Ajayi and Samuel-Foo 2021; Bernard et al. 2022). The production of secondary metabolites has been linked with improved insect pest tolerance. High densities of glandular trichomes on the inflorescences may decrease the mobility and foraging efficiency of some aphid species (López Carretero et al. 2022). In a feeding preference assay, it was demonstrated that Manduca sexta exhibits a preference for feeding on leaves with low CBD over high CBD, and hornworms fed with high-CBD content leaves suffered increased mortality (Park et al. 2019).
While most feeding events have negative effects and contribute to yield reductions due to plant damage, several groups have reported “overcompensation” in plant growth and cannabinoid accumulation as a result of pest damage. The European corn borer (Ostrinia nubilalis) is an insect that bores into larger stalks and can structurally weaken the plant; however, more branching, increased biomass, and improved seed yields were observed in industrial hemp following a corn borer infestation (Small et al. 2007). Similarly, increased concentration of all terpenes and cannabinoids was observed in response to the two-spotted spider mite (Tetranychus urticae), a leaf-feeding pest. Infestation with Tetranychus urticae, maintained until the late vegetative phase, significantly increased levels of CBG, CBC, and THC in the leaves (by 26%, 41%, and 52%, respectively) (Kostanda and Khatib 2022). The practical significance of such “overcompensation” response to insect damage is still controversial and may depend on both the cannabis strain and pest species. For instance, no changes in cannabinoid levels were found by infestation with M. sexta or mechanical wounding after 5 days (Park et al. 2022).
Plants grown at high densities compete for light, water, nutrients, and other resources. Plant–plant interactions depend on a complex array of signals including light quality and quantity, volatile organic compounds that carry information about neighbouring plants, root exudates, and mechanical interactions via physical touch (Huber et al. 2021; Wang and Callaway 2021; Brosset and Blande 2022). Examining the effects of plant density in C. sativa is of agronomic importance and has been examined in several recent studies. Meta-analysis of cannabis yields reported in the scientific literature suggests that plant overcrowding may decrease THCA amounts and total yield in drug-type C. sativa (Backer et al. 2019), likely through decreased light penetration within the plant canopies (Vanhove et al. 2011). Firm evidence for optimal crop density for biomass and cannabinoid yields is yet to be established, and there are no insights on the physiological processes that underpin plant–plant interactions of C. sativa.

Conclusions and future directions

Cannabis is an emerging crop of growing economic importance, and the recent progress on all aspects of its biology has revealed exciting challenges ahead. Recent years have brought new advances in elucidating the complex chemistry of the C. sativa secondary metabolites, the genetics that govern their accumulation, and breeding of new cultivars with tailored cannabinoid and terpene profiles. Here, we propose that equally important are detailed morphological, physiological, and molecular studies characterizing how C. sativa interacts with its environment.
The role of cannabinoids in the plant is still not fully understood but the recent work summarized here suggests that the accumulation of these compounds does respond to environmental cues. Initial studies suggest that, as a species, C. sativa is resilient to many environmental stressors and it has been tempting to link the accumulation of cannabinoids with stress resilience (e.g., in Gülck and Møller 2020). While previous studies have suggested that these metabolites have a protective role, there is a paucity of experimental data to fully support this hypothesis. In addition, the relationship between the occurrence of environmental stress and cannabinoid accumulation appears to be complex and likely depends on the intensity of the stressor, crosstalk with other environmental factors, developmental stage, and the genetic background of the plant. A significant pitfall in our current insights in the cannabis biology is the usage of “industry-favourite” strains in research, which are often of ill-defined parentage and genetics. Thus, one of the first challenges will be to standardize the cultivars used in further research to ensure that studies are comparable and repeatable.
In the following section, we provide several suggestions to guide future research on elucidating the complex relationship between environmental stress and cannabinoid accumulation:
1.
Transgenic approaches: The first report of efficient Agrobacterium transformation (Galán-Ávila et al. 2021) and CRISPR-Cas9-mediated modification of the C. sativa genome were recently reported (Zhang et al. 2021b). These advances have opened the doors for development of genomic tools to understand cannabis biology. Do plants that have higher cannabinoid levels exhibit increased stress resilience? Are certain secondary metabolite profiles conductive towards stress resilience? C. sativa transformants with tailored secondary metabolite profiles in the same genetic background could be an excellent way to answer these questions and elucidate the roles of cannabinoids in the plant.
2.
Regulation of cannabinoid metabolism: Future efforts in understanding the intricate networks that underlie cannabinoid biosynthesis should focus on understanding the genetic regulation of key genes involved in the process and the post-translational regulation of their protein products. The first reports on the transcriptional regulation of cannabinoid biosynthesis have identified several regulatory elements (WRKY, bHLH, and MYB transcription factors) in the promoters of key genes (Bassolino et al. 2020; Liu et al. 2021). Similarly, there are only a few studies that have characterized the activity of THCAS/CBDAS, suggesting that the activity of these enzymes depends on temperature and pH (Zirpel et al. 2018). These studies imply a complex regulation of secondary metabolite biosynthesis, an excellent topic for future research.
3.
Systematic study of cannabis biology: CannabisGDB is the first integrated functional genomic database for C. sativa, which includes multiple genome sequences, transcriptomic data sets, and liquid chromatography mass spectral projects quantifying cannabinoid levels (Cai et al. 2021). Recent advances in -omics techniques, combined with advances in artificial intelligence, will be instrumental in pooling data and insights from the cannabis research community. Community resources that provide the data and the tools to mine it have brought about important insights into other crop species. Such resources, specifically for C. sativa, will benefit not only the “stress biologists” but also the entire cannabis research community.
Current work suggests that carefully applied stressors may change the cannabinoid profiles of the plant; however, this often happens at the expense of biomass yields. Thus, a balance must be maintained to maintain biomass and promote secondary metabolite accumulation. This balancing act can only be achieved by further study on the physiology and molecular biology of C. sativa.

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cover image Botany
Botany
Volume 101Number 8August 2023
Pages: 318 - 332

History

Received: 13 April 2023
Accepted: 29 June 2023
Accepted manuscript online: 11 July 2023
Version of record online: 27 July 2023

Notes

This paper is part of a special issue entitled “Research Advances on Cannabis”.

Data Availability Statement

This manuscript does not report original data.

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Key Words

  1. Cannabis
  2. cannabinoids
  3. secondary metabolites
  4. abiotic stress
  5. biotic stress

Authors

Affiliations

Josephine Payment
Department of Biology, University of Ottawa, Ottawa, ON, Canada
Author Contributions: Methodology, Writing – original draft, and Writing – review & editing.
Department of Biology, University of Ottawa, Ottawa, ON, Canada
Author Contributions: Conceptualization, Funding acquisition, Supervision, Validation, and Writing – review & editing.

Author Contributions

Conceptualization: MC
Funding acquisition: MC
Methodology: JP
Supervision: MC
Validation: MC
Writing – original draft: JP
Writing – review & editing: JP, MC

Competing Interests

The authors declare there are no competing interests.

Funding Information

The work was supported by funds from the Natural Sciences and Engineering Research Council of Canada: Collaborative Research and Training Experience (NSERC: CREATE; Grant 543319-2020). JP was supported by an Ontario Graduate Scholarship (OGS).

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