A tale of two cannabinoids: The therapeutic rationale for combining tetrahydrocannabinol and cannabidiol

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Summary

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.

Introduction

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” [1]. 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 [2], and both are partial agonists on the CB1 receptor. Pertwee [3] 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 [4], 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, Δ9-tetrahydrocannabinol (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 [5], 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 [6] in an elegant ‘entourage effect’ [7] 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 [8] 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 [9] 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 [10]. 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 [11]. In most instances, synthetic THC is considered by patients to be more productive of intoxicating and sedative adverse effects [12], 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 [16], anti-psychotic effects [17], modulates metabolism of THC by blocking its conversion to the more psychoactive 11-hydroxy-THC [18], prevents glutamate excitotoxicity, serves as a powerful anti-oxidant [19], and has notable anti-inflammatory and immunomodulatory effects [20] (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 [21]. Thus, CBD may prove to be the first clinical pharmaceutical to modulate endocannabinoid function.

The remainder of this paper will focus on the interactions of the two compounds when administered simultaneously and explore the theoretical advantages of so doing in clinical application.

Section snippets

A review of animal studies of simultaneously administered THC and CBD

A great deal of the early research pertaining to interactions of THC with other phytocannabinoids was performed in Brazil in the 1970s. The seminal work was that of Karniol and Carlini [22] who examined various animal species with differing low-moderate doses of THC and CBD administered IP. To summarise, CBD blocked certain effects of THC: catatonia in mice, corneal arreflexia in rabbits, increased defaecation and decreased ambulation in rats in the open field after chronic administration, and

A review of human studies of THC and CBD simultaneously administered

Administration of CBD orally (up to 300 mg) and IV (up to 30 mg) in volunteers were felt to be inactive in early experiments [31], with similar conclusions after IV infusion by another group [32].

In Brazil in 1974, effects of THC up to 30 mg and CBD up to 60 mg orally were studied in varying ratios in blinded fashion in 40 male subjects [33]. CBD at doses 15–60 mg evidenced few effects of its own, but effectively countered effects of 30 mg of THC including tachycardia, disturbed time tasks and strong

Cannador

A recent small clinical trial of THC and an oral cannabis extract (Cannador) was performed with 16 subjects. Neither was observed to reduce spasticity, and adverse events were reported as greater in the extract group even at low dosages [43]. Numerous criticisms were subsequently voiced in this regard [44] such that the plant extract was poorly categorised, and employed sub-optimal oral administration with no real dose titration. An additional study in Switzerland [45] with more patients and

Experience with oromucosal cannabis based medicines

Sativex® is a highly standardised medicinal product composed of liquid carbon dioxide extracts from selected strains of cloned cannabis plants cultivated employing Good Agricultural Practice (GAP), to provide high and reproducible yields of THC and CBD. Sativex is a 1:1 combination from two clonal cannabis cultivars yielding a high THC extract (Tetranabinex®) and a high CBD extract (Nabidiolex®). The dried of unfertilised female flowers are extracted and refined utilising Good Manufacturing

Neuroprotection

The seminal work describing the neuroprotective roles of THC and CBD has been that of Hampson et al. [73]. Both phytocannabinoids protected equally against glutamatergic neurotoxicity mediated by NMDA, AMPA, or kainate receptors, and this effect was not antagonized by SR1414716A, thus demonstrating it to be operative independently of cannabinoid receptor activation. The group additionally investigated the effects of THC and CBD on reactive oxygen species (ROS), finding them equal to that of the

Cannabinoids and dependency

A simple perusal of the medical literature will confirm that considerable concern continues in context as to the drug abuse liability of THC preparations. However, that substance in isolation has proven to pose little risk [12]. To the extent that rapidly rising serum levels promote reward and addictive potential of a given pharmaceutical [88], it is certainly arguable that the addition of CBD to THC would reduce psychoactive attraction, and that an oromucosal delivery eliminates the steep

Conclusion

Various publications have presented the position that THC accounts for the main effects [100], the analgesic and other medicinal benefits [101] of cannabis. This paper supports a distinct view that CBD and perhaps other cannabis components [6] achieve synergy with THC [102] consisting of potentiation of benefits, antagonism of adverse effects, summation (à la the entourage effect), pharmacokinetic advantages (in CBD suppression of 11-hydroxylation of THC), and metabolism (e.g., lower toxicity

Conflict of interest/role of funding Source

The author has been a consultant for GW Pharmaceuticals since 1998, and has received grants-in-aid, travel expenses, research support, stock options and salary in this regard.

Search strategy and selection criteria

References for this review were identified by searches of PubMed/National Library of Medicine database from 1966 to June 2005 for articles pertinent to cannabidiol and its combination with THC in English, French, Spanish, Portuguese and Italian. Additional sources were identified in the author’s extensive personal library of books and files.

Acknowledgements

The author thank Richard Musty for suggesting certain references and Emma Brierley and Alice Mead for suggested revisions.

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