# Non-Cannabinoid Metabolites of _Cannabis sativa_ L. with Therapeutic Potential
## 1 Introduction  
A central Asian site of domestication of the cannabis plant is often cited [1]. The plant's medical value was first recorded in the Pen Ts'ao Ching, the Chinese pharmacopoeia--the world's oldest, compiled in the Han dynasty, first or second century A.D. [1]. The cannabis plant, its resin, and some derivatives of its compounds have been used in traditional Eastern medicine. Uses include, for recreation, due to its hallucinogenic/hypnotic effects; for religious celebrations and meditative purposes; industrially for fibers, textiles and ropes; and medicinally as an analgesic anticonvulsant, antidiarrhoeal, sedative, relaxant, anxiolytic, antibacterial, and antioxidant, and as treatment for tetanus, epilepsy and delirium tremens. The cannabis plant produces an estimated 545 [2] chemical compounds. The main bio-genetic classes of compounds produced are shown in Table 1 below. These include primary metabolites, such as amino acids, fatty acids, vitamins, sugars, and proteins, and secondary metabolites produced in trichomes, the cell's factory. Primary metabolites providenutritional value. Secondary metabolites also provide nutritional value and include approximately 120 terpenoids (61 monoterpenes, 52 sesquiterpenoids, and 5 triterpenoids [2], over 26 flavonoids [2], lignans, stilbenes and derivatives such as dihydro-resveratrol (3,5,4'-trihydroxybibenzyl) [3], cannabinaceous alkaloids such as cannabisativine and anhydro-cannabisativine [4], and 20 steroids [2]), dihydrophenanthrenes, glycoproteins, and dibemzyls [5,6]. In addition to sharing analgesic, antimicrobial anticancer, anti-inflammatory, and neuroprotective properties, a majority also share antioxidant capabilities [7]. During many pathological conditions and diseases processes such as age-related inflammatory and autoimmune diseases, asthma, atherosclerosis, cancer, chronic obstructive pulmonary disease, hypertension, ischemia/perfusion, diabetes, HIV and dementia [8], the cells of the body accumulate high levels of toxic reactive oxygen species (R.O.S. )/free radicals in comparison to antioxidants [9]. This imbalance can cause significant damage to cell structures [9]. Antioxidants mitigate excessively produced reactive oxygen species within the cells, and in doing so, reduce the oxidative stress in cells [10]. Antioxidants may therefore have therapeutic applicability against many human diseases including but not limited to cancer, viral infections, cardiovascular diseases and inflammatory diseases [10]. Natural antioxidants may also be revered due to their safer side effect profile compared to synthetic antioxidants used in preventative medicine and in the food industry [10]. The biosynthesis of the non-cannabinoids in cannabis is driven by pyruvate/acetyl-CoA for the terpenes via the plastidial deoxysylulose phosphate/methyl-erythitol phosphate (DOXP/MEP) and cytoplasmic MVA pathways [2], and \(p\)-counarli-CoA via the phenyl-propanoid pathway [2] for flavonoids [2]. The synthesis of cannabinoids is via the precursor molecule olivetolic acid (OLA) and the polyketide pathway, and another precursor molecule, olivetolic acid (GPP) and the plastidial deoxysylulose phosphate/methyl-erythitol phosphate (DOXP/MEP) pathway [2]. These processes are simplified in Figure 1 below. In addition to having unique organoleptic properties [12], terpenes provide a wide range of therapeutic benefits to humans, secondary metabolites, particularly terpenes and flavonoids, play a primary role in a plant's defenses against hostile environments, herbivores and phytophagous insects. The identified non-cannabinoid metabolites of cannabis are discussed in more detail in the ensuing sections.