Biosynthesis and Medicinal Value of Key Cannabinoids

The approximate numbers of cannabis related compounds are significant: over 500 unique compounds, >100 unique cannabinoids, >100 terpenes, and many more flavinoids. The bounty of prospective compounds with therapeutic value is likewise impressive. Moreover, the synergy or "entourage effect" that multiple compounds may exhibit adds another dimension to this mix -- a concept that is gaining significant support.

Stratifying the therapeutic value of individual compounds, and the subsequent combinations of multiple compounds, will continue to rely upon improvements in cannabis processing and testing methods and equipment. As these methods become more consistent, reliable, and robust, therapeutic products will in turn become safer and more efficacious.

The major cannabinoids

Several key cannabinoids have been the focus of investigations and as such have been reasonably well defined chemically and medicinally.

Tetrahydrocannabinol (THC) is the most abundant cannabinoid in cannabis and is responsible for the observed psychoactive effects. The compound has also been associated with a sizable number of therapeutic applications ranging from management of nausea and appetite, to pain relief and sleep disorders, to anti-inflammatory and gastrointestinal disorders. Notably, THC has also been linked to the treatment of a variety of severe neurological diseases and disorders such as Multiple Sclerosis, Dementia, and others.

Sources of THC and CBD

THC, in the decarboxylated form, acts as a partial agonist of type-1 (CB1) and type-2 (CB2) cannabinoid receptors. It is produced in the trichomes and is present in flowers, leaves, and other areas particularly of the female plant. Other cannabinoids such as CBD (another highly prominent cannabinoid) are present in higher concentrations in hemp. Genetic lineage (and strain specificity) dictates the relative concentrations of THC, CBD, and other cannabinoids and therefore therapeutic potential.

Biosynthesis of THC and CBD

The biosynthetic machinery for THC and CBD natural production are similar up to a certain key stage. The common precursor, Olivetol or Olivetolic ecid, is processed by aromatic prenyltransferase to form Cannabigerolic acid (CBGA). At this point, the enzymes THCA synthase or CBDA synthase process the compound into either THCA or CBDA. These products then undergo non-enzymatic decarboxylation (through light or heat treatment) to form the bioactive forms THC or CBD. It is the expression levels of THCA synthase or CBDA synthase which dictate the relative production of the end compounds -- and in effect the medicinal potential.

THC mode of action

THC functions as both CB1 ad CB2 cannabinoid receptor agonists in the brain and other tissues. It's binding causes the inhibition of adenylate cyclase activity, the modulation of ion channels, and the stimulation of mitogen-activated protein kinases (MAPKs). CB1 rich areas of the brain include those that regulate appetite, memory, fear, motor responses, and others. Whereas, CB2 rich areas are mainly localized to macrophages and other immune cells including microglia and osteoblasts. The effect of THC in neuronal tissues stem from the enhancement of endocannabinoids and the modulation of synaptic activities. A greater understanding of these endogenous compounds and the systems they impact will lead to a more complete picture of how THC exacerbates or inhibits key processes -- and therefore influences disease.

CBD mode of action

CBD on the other hand does not bind nor influence either of the CB receptors directly (it has very low affinity for either type). Rather, CBD interferes with the deactivation of the endocannabinoid compound anandamide, either by influencing enzymatic breakdown or uptake, and can therefore indirectly affect CB1 activation. The complete absence of CB2 interaction translates to the absence of both the therapeutic as well as the undesirable side effects, such as paranoia and memory loss -- effects associated with THC. CBD has a host of additional activities beyond the endocannabinoid system, including modulation of receptors and neurotransmitters associated with pain and inflammation, as well as anti-oxidation and neuroprotective effects.

Medicinal outlook

Although THC and CBD share similar upstream biosynthesis origins, the end compounds have dramatically different modes of action and biological effects. A greater understanding of the molecular genetic basis of cannabinoid production will lead to more precise application of particular plant strains and end products for specific medical uses. Moreover, increases in high quality research will more clearly define the target systems and will in turn lead to better therapeutics.

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Updated July 2019