A tale of two cannabinoids : The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol
Ethan Russo & Geoffrey W. Guy
Medical Hypotheses, 2006, 66, 234–246
doi : 10.1016/j.mehy.2005.08.026
This study examines the current knowledge of physiological and clinical effects of tetrahydrocannabinol (THC) and cannabidiol (CBD) and presents a rationale for their combination in pharmaceutical preparations. Cannabinoid and vanilloid receptor effects as well as non-receptor mechanisms are explored, such as the capability of THC and CBD to act as anti-inflammatory substances independent of cyclo-oxygenase (COX) inhibition. CBD is demonstrated to antagonise some undesirable effects of THC including intoxication, sedation and tachycardia, while contributing analgesic, anti-emetic, and anti-carcinogenic properties in its own right. In modern clinical trials, this has permitted the administration of higher doses of THC, providing evidence for clinical efficacy and safety for cannabis based extracts in treatment of spasticity, central pain and lower urinary tract symptoms in multiple sclerosis, as well as sleep disturbances, peripheral neuropathic pain, brachial plexus avulsion symptoms, rheumatoid arthritis and intractable cancer pain. Prospects for future application of whole cannabis extracts in neuroprotection, drug dependency, and neoplastic disorders are further examined. The hypothesis that the combination of THC and CBD increases clinical efficacy while reducing adverse events is supported.
Cannabinoids refer to a heteromorphic group of molecules that demonstrate activity upon cannabinoid receptors and are characterised by three varieties: endogenous or endocannabinoids, synthetic cannabinoids, and phytocannabinoids, which are natural terpenophenolic compounds derived from Cannabis spp.
In recent years, scientists have provided elucidation of the mechanisms of action of cannabis and THC with the discovery of an endocannabinoid ligand, arachidonylethanolamide, nicknamed anandamide, from the Sanskrit word ananda, or ‘‘bliss’’ . Anandamide inhibits cyclic AMP mediated through G-protein coupling in target cells. Early testing of its pharmacological action and behavioural activity indicate similarity to THC , and both are partial agonists on the CB1 receptor. Pertwee  has examined the pharmacology of cannabinoid receptors in detail. CB1 receptors are most densely demonstrated in the central nervous system, especially in areas subserving nocicecption, short-term memory, and basal ganglia, but are also found in the peripheral nerves, uterus, testis, bones and most body tissues. CB2 receptors, in contrast, are mostly found in the periphery, often in conjunction with immune cells, but may appear in the CNS particularly under conditions of inflammation in association with microcytes. Additional non-CB1 and non-CB2 receptors in endothelial and other tissues are hypothesised , but not yet cloned. Further research has elucidated analgesic mechanisms of cannabinoids, which include effects on numerous neurotransmitter systems and interactions with the endogenous opioid system.
This paper will focus on the biochemical and clinical effects of two phytocannabinoids, D9- tetrahydro cannabinol (THC) (Fig. 1), the main psychoactive component of cannabis, and its non-psychoactive but highly physiologically relevant isomer, cannabidiol (CBD) (Fig. 1). While it was originally thought that CBD was the metabolic parent to THC in the cannabis plant, rather, they are both biosynthesised as THCA and CBDA from a cannabigerolic acid precursor (Fig. 2) according to genetically determined ratios , and then decarboxylated by heat or extraction to produce THC and CBD proper. It is interesting to note that the phytocannabinoids can be considered as half-siblings to the essential oil terpenoids with which they share a geranyl pyrophosphate precursor in the glandular trichomes of the plant where they are produced. It is felt by some authorities that these terpenoids share important modulatory and pharmacological effects with trace cannabinoids  in an elegant ‘entourage effect’  that may account for synergistic activity of cannabis extracts over that of isolated components. Therapeutic benefits are thus added,whilst some adverse effects are attenuated. In this regard, Carlini  determined that cannabis extracts produced effects two or four times greater than that expected from their THC content, based on animal and human studies. Similarly, Fairbairn and Pickens  detected the presence of unidentified ‘powerful synergists’ in cannabis extracts, causing 330% greater activity in mice than THC alone. An unidentified component of the plant (perhaps linalool?) also showed anticonvulsant properties of equal potency to cannabinoids . Finally, although anecdotal to some degree, extensive surveys in the USA comparing patients’ subjective responses with synthetic THC as Marinol supports a preference for whole cannabis products . In most instances, synthetic THC is considered by patients to be more productive of intoxicating and sedative adverse effects , characterised by the authors as (p. 95), ‘dysphoric and unappealing’.
The effects of THC are well known, and include analgesia, intoxication, short-term memory loss, muscle relaxant and anti-inflammatory effects [3,13] (summarised in Fig. 3, with corresponding references).
The pharmacological profile of CBD has received three recent excellent reviews [14,15]. Briefly stated, CBD has anti-anxiety actions , anti-psychotic effects , modulates metabolism of THC by blocking its conversion to the more psychoactive 11-hydroxy-THC , prevents glutamate excitotoxicity, serves as a powerful anti-oxidant , and has notable anti-inflammatory and immunomodulatory effects  (summarised in Fig. 3 with corresponding references). Notably, CBD has recently been shown to act as a TRPV1 agonist of potency equivalent to capsaicin, while also inhibiting reuptake of anandamide and its hydrolysis . Thus, CBD may prove to be the first clinical pharmaceutical to modulate endocannabinoid function.