entourage effect between the various cannabinoids (Mechoulam and Ben-Shabat
1999 ).
The vast majority of Cannabis’ therapeutic activity is attributed to the
cannabinoids, a class of compounds unique to cannabis, with most research focused
on THC, thefirst and most famous cannabinoid. More recently, work has been
performed supporting the therapeutic potential of a related cannabinoid,
cannabidiol. However, cannabis contains over 70 related cannabinoids only a
handful of which have been studied for beneficial pharmacological activity. The
few that have been studied including CBC, CBG, CBN, CBDV, THCV are very
promising for development for the treatment of a number of diseases including
diabetes, cancer, neurodegenerative diseases and inflammation (Izzo et al. 2009 ).
In addition, it is important to remember that cannabinoids are not the only
bioactive compounds found in cannabis. A number of terpenoids including limo-
nene, pinene, caryophyllene, and linalool have been described in cannabis to
possess significant therapeutic activity even acting synergistically together with
cannabinoids (Russo 2011 ). The synergistic effect may be similar to the entourage
effect documented in endocannabinoids, where a mixture of non-active compounds
indirectly increase bioactivity primarily by competing with active compounds for
enzymatic deactivation (Mechoulam and Ben-Shabat 1999 ).
Because of the importance of cannabinoid diversity to treat different therapeutic
targets and the implications of the synergistic effects as well as the aforementioned
need to standardize the natural chemical variation, a better understanding of the
factors affecting biosynthesis of cannabinoids in cannabis is needed.
Although it has been extensively studied primarily dealing with the genetic
inheritance of cannabinoid production, very little work has been done studying the
ecological factors influencing the chemical composition and related therapeutic
activity of cannabis. While the exact ecological role of cannabinoids in cannabis is
not clear, the little that is known suggests that environmental stress plays an
important role in cannabinoid biosynthesis.
The environmental stresses implicated in cannabinoid biosynthesis can be
divided into 2 categories: abiotic or biotic. As previously mentioned, abiotic
stressors, or elicitors, include nutrient deficiency, water and temperature stress,
photo-radiation, and heavy metal stress. Biotic elicitors include insect feeding as
well as fungal and bacterial pathogens and the related hormones involved in their
response.
21.3 Nutrient Deficiency
While plant nutrition is a vital factor in the production of secondary metabolites, its
role in the production of cannabinoids in cannabis is unclear. In general, a corre-
lation has been suggested between increased mineral content of macronutrients
including nitrogen, calcium (Haney and Kutcheid 1973 ) iron (Kaneshima et al.
1973 ), and magnesium (Latta and Eaton 1975 ) and increased THC content.
442 J. Gorelick and N. Bernstein