Since antiquity, various preparations of the plant Cannabis sativa have been used for medicinal and religious purposes. Widespread across ancient Asia, cannabis served as an antiemetic, anticonvulsant, antibiotic, anti-inflammatory, analgesic, anesthetic, antispasmodic, diuretic, digestive, appetite stimulant, antitussive, expectorant, and aphrodisiac (Zuardi 2006).With origins as far back as 4000 BC, Chinese pharmacopoeias documented the medicinal use of cannabis, outlining its effectiveness in the treatment of pain, constipation, menstrual cramps, and malaria (Li 1978). However, these sources noted that, when taken in excess, cannabis could yield “visions of devils” (Li 1978, p. 18). Its psychoactive properties were also described in ancient India, where they were associated with religious rituals, and the sacred text Atharva Veda included cannabis as one of the five sacred plants for its ability to convey “happiness,” “joy,” and “freedom” (Touw 1981, p. 25).

Additionally, it is well documented that people used cannabis to alleviate symptoms of mood disorders such as anxiety, depression, mania, and hysteria (Mechoulam et al. 1970, Russo & Guy 2006). Medical interest in the plant spread throughout Europe and North America in the nineteenth century (Grinspoon & Bakalar 1995), but despite the apparent therapeutic potential of cannabis for affective disorders and innumerous other ailments, its use in Western medicine decreased significantly in the early twentieth century (Zuardi 2006). The decline of medicinal cannabis was largely due to several factors. In particular, researchers may have had difficulty in achieving reliable therapeutic effects, as drug extracts were made from different strains of the plant and with varying methods of preparation (Fankhauser 2002).

Because the active constituents of cannabis had not been isolated, other medications replaced cannabis for its recommended uses, and it was eventually removed from Western pharmacopoeias. Finally, concerns regarding the psychoactive effects of cannabis and its potential impairment of learning and memory prompted many legal restrictions, obstructing academic research on the plant (Zuardi 2006, Hill et al. 2012). Systematic quantitative research on the active constituents of cannabis did not being in earnest until modern separation techniques made it possible to distinguish among the closely related molecular compounds within the plant (Mechoulam & Parker 2013). Although scientists eventually isolated over 60 phytocannabinoids (pCBs), the two major active constituents identi- fied were 9-tetrahydrocannabinol (THC) (Gaoni & Mechoulam 1964) and cannabidiol (CBD) (Mechoulam & Shvo 1963).

THC is the prominent psychoactive pCB of the plant and mediates the rewarding properties of cannabis (Huestis et al. 2001); CBD, in contrast, does not have reinforcing effects and has low abuse potential (Katsidoni et al. 2013, Parker et al. 2004). Despite these differences in psychoactivity, THC and CBD are produced by codominant alleles of the same gene locus and segregate according to simpleMendelian inheritance, yielding three cannabis chemovariants in a 1:2:1 ratio of pure THC, mixed THC/CBD, and pure CBD (de Meijer et al. 2003). Currently, although the chemovariants containing predominantly THC are used primarily for recreational purposes, synthetic THC (e.g., dronabinol, nabilone) has been approved for the alleviation of nausea and vomiting as well as for appetite stimulation in cancer and HIV/AIDS patients (Hill et al. 2012).

Perhaps of greater therapeutic interest are the chemovariants containing a 1:1 ratio of THC to CBD or those containing predominantly CBD. As the first licensed medicinal whole cannabis extract [in Canada, the United Kingdom (UK), Germany, Spain, Denmark, and New Zealand], SativexR (GW Pharmaceuticals, UK) has indications for pain and spasticity associated with multiple sclerosis (Barnes 2006, Perras 2005) and an approximate 1:1 ratio of THC to CBD. Importantly, this ratio reduces the unwanted central actions of THC (Russo & Guy 2006) and minimizes abuse liability (Schoedel et al. 2011). This has renewed interest in investigation of synergistic or “entourage” effects of pCBs administered together (Ben-Shabat et al. 1998, Mechoulam & Ben-Shabat 1999) and highlighted the need for systematic examination of pCBs other than THC. Although CBD is the second most common pCB, there has been a shortage of experimental inquiry into its mechanisms of action and therapeutic effects. When administered along with THC, CBD reduces subjective ratings of intoxication (Robson 2011, Schoedel et al. 2011), ameliorates cognitive and behavioral impairment (Wade et al. 2004), and reverses THC-induced anxiety (Zuardi et al. 1982).

However, CBD might be worth investigating not just for its ability to antagonize the effects of THC but in its own right as a pharmacological agent. Early preclinical studies demonstrate promising treatment effects of CBD for seizure disorders (Devinsky et al. 2014), and along with the development of CBD-based pharmacotherapies (e.g., EpidiolexR , GW Pharmaceuticals), clinical trials are under way to evaluate the strength of its treatment effects for medically intractable pediatric epilepsy (Cilio et al. 2014, Devinsky et al. 2014). The potential for wide-ranging therapeutic action of CBD in central nervous system disorders extends from emerging evidence of its diversity of receptor targets, including those beyond the endocannabinoid (eCB) system. Here, we review the pharmacological actions of CBD that may make it suitable as a treatment for an array of motivational and affective disorders such as drug addiction, anxiety, and depression.

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Beyond the CB1 Receptor: Is Cannabidiol the Answer for Disorders of Motivation?

Natalie E. Zlebnik and Joseph F. Cheer