Before addressing cannabinoid crystal polymorphism, it is useful to first consider which cannabinoids in Cannabis have even been analyzed as single crystalline entities? To answer this question, a literature search was performed using the Cambridge Structural Database as well as the SciFinder® chemistry database. Of the many cannabinoids in Cannabis, only a few have been characterized by X-ray crystal analysis and they include: delta-9-tetrahydrocannabinolic acid A (THCA-A) (Skell et al. 2021), delta-9-tetrahydrocannabinolic acid B (THCA-B) (Rosenqvist and Ottersen 1975), cannabidiol (CBD) (Mayr et al. 2017; Jones et al. 1977; Ottersen et al. 1977a), cannabinol (CBN) (Ottersen et al. 1977b), and cannabigerol (CBG) (Fettinger et al. 2020). Regarding polymorphism in general, it can be seen in Fig. 1 that growth of the crystal polymorphism literature (both journal articles and patents in SciFinder®) has dramatically increased, nearly quadrupling in the past 20 years. An exhaustive literature review was also performed to learn if any cannabinoid crystal polymorphs have been described? This search was conducted not only on the large number of publications captured under “cannabinoids” in general but also the very specific cannabinoids: THCA-A, delta-9-tetrahydrocannabinol (THC), cannabidiolic acid (CBDA), CBD, cannabigerolic acid (CBGA), CBG, cannabinolic acid (CBNA), CBN, cannabichromenic acid (CBCA), and cannabichromene (CBC). Unfortunately, this effort was greatly complicated by the many papers related to cannabinoid gene polymorphism. Excluding the special case of cocrystal polymorphs (Aitipamula et al. 2014) and any errors of omission due to the complexity of the literature search, it would appear that no fully characterized Cannabis cannabinoid crystal polymorph has yet been reported. However, there have been several intriguing clues in the literature that cannabinoid crystal polymorphism may well be possible (Fig. 2).

Interestingly, the cannabinoid receptors have been an important docking location for several structurally diverse compounds which have exhibited crystal polymorphism. The lipid N-palmitoylethanolamine [1] is an agonist at the type 2 cannabinoid receptor (CB-2). Two crystal polymorphs (designated α and β) of it were discovered and characterized by X-ray crystallography (Kamlekar and Swamy 2006). Also, the synthetic heterocycle rimonabant [2] is an inverse agonist at the type 1 cannabinoid receptor (CB-1) and has also demonstrated crystal polymorphism (Fours et al. 2015). However, even more compelling and direct evidence suggests that the basic cannabinoid structural framework itself has the capacity for crystal polymorphism as well. It was discovered 40 years ago that the synthetic 9-ketocannabinoid derivative nabilone [3] displayed crystal polymorphism. One of the earliest studies utilizing solid state carbon-13 NMR spectroscopy characterized several crystal polymorphic forms of nabilone (Byrn et al. 1985). Furthermore, the THC naphthoyl ester derivative [4] was just reported to exist in as many as eight different crystal polymorphic forms, designated A-H (Hallow et al. 2021). These separate crystal structures were analyzed by combinations of differential scanning calorimetry (DSC), thermal gravimetric analysis (TGA) as well as powder X-ray diffraction (PXRD). One crystal polymorph of 4 reportedly had a penchant for easily forming solvates and several of its crystal polymorphs were found to be interconvertible.