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Cannabidiol (CBD) has been recently covered in the media, and you may have even seen it as an add-in booster to your post-workout smoothie or morning coffee. What exactly is CBD? Why is it suddenly so popular?

CBD is readily obtainable in most parts of the United States, though its exact legal status is in flux. All 50 states have laws legalizing CBD with varying degrees of restriction, and while the federal government still considers CBD in the same class as marijuana, it doesn’t habitually enforce against it. In December 2015, the FDA eased the regulatory requirements to allow researchers to conduct CBD trials. Currently, many people obtain CBD online without a medical cannabis license. The government’s position on CBD is confusing, and depends in part on whether the CBD comes from hemp or marijuana. The legality of CBD is expected to change, as there is currently bipartisan consensus in Congress to make the hemp crop legal which would, for all intents and purposes, make CBD difficult to prohibit.

How is cannabidiol different from marijuana?

CBD stands for cannabidiol. It is the second most prevalent of the active ingredients of cannabis (marijuana). While CBD is an essential component of medical marijuana, it is derived directly from the hemp plant, which is a cousin of the marijuana plant. While CBD is a component of marijuana (one of hundreds), by itself it does not cause a "high." According to a report from the World Health Organization, "In humans, CBD exhibits no effects indicative of any abuse or dependence potential…. To date, there is no evidence of public health related problems associated with the use of pure CBD."

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Side effects of CBD include nausea, fatigue and irritability. CBD can increase the level in your blood of the blood thinner coumadin, and it can raise levels of certain other medications in your blood by the exact same mechanism that grapefruit juice does. A significant safety concern with CBD is that it is primarily marketed and sold as a supplement, not a medication. Currently, the FDA does not regulate the safety and purity of dietary supplements. So, you cannot know for sure that the product you buy has active ingredients at the dose listed on the label. In addition, the product may contain other (unknown) elements. We also don’t know the most effective therapeutic dose of CBD for any particular medical condition.

The cannabis plant has two main subspecies, Cannabis indica and Cannabis sativa, and they can be differentiated by their different physical characteristics. Indica-dominant strains are short plants with broad, dark green leaves and have higher cannabidiol content than the sativa plants in which THC content is higher. Sativa-dominant strains are usually taller and have thin leaves with a pale green colour. Due to its higher THC content, C. sativa is the preferred choice by users. It is a complex plant with about 426 chemical entities, of which more than 60 are cannabinoid compounds [Dewey, 1986]. The four major compounds are d-9-THC, CBD, d-8-THC and cannabinol, which have been most researched [Pertwee, 1997, 2008; Pamplona and Takahashi, 2012].

Because of the reported links between the schizotypal personality and schizophrenia, this type of personality disorder has come under scrutiny in examining the role of cannabis in producing psychotic symptoms. Indeed, it has been shown that people scoring high in schizotypy who use cannabis are more likely to have psychosis-like experiences at the time of use, together with unpleasant side effects [Barkus et al. 2006]. This study has been replicated and it has been confirmed that those with schizotypal personality disorder carry a higher risk of experiencing psychotic symptoms with cannabis use [Stirling et al. 2008]. Most recently, another study has provided further support for a strong association between early cannabis use and the development of schizophrenia spectrum disorder symptoms [Anglin et al. 2012].

Functions of the endocannabinoid receptor system

However, the functionalities of the CB1Rs are not always straightforward due to complex interactions with the other neurotransmitter systems. These are related to CB1Rs and CB2Rs being members of the super family of G-protein-coupled receptors (GPCRs) [Pertwee et al. 2010]. GPCRs sense an external molecule outside the nerve cell and by contact with the molecule can signal transduction pathways, which ultimately lead to cellular responses. External ligands such as d-9-THC, various synthetic compounds and endocannabinoids such as anandamide can activate these receptors [Pertwee et al. 2010]. Interestingly some alkylamides from the Echinacea plant can also bind to the CB2Rs even more strongly than the endogenous cannabinoids [Raduner et al. 2006]. The mechanism of action for CBD is not yet clear, as this compound does not bind to CB1Rs or CB2Rs [Tsou et al. 1998; Hayakawa et al. 2008].

Normally GPCRs are linked together to form a receptor complex. However, the signalling effects can be complex due to CB1Rs forming heteromers, which can be defined as having different parts such as subunits, with two or more other GPCRs, particularly if they are densely expressed in the same neuron. For instance, a CB1R can form a heteromer with dopamine D2 receptor, or in another instance it can also form a heteromer with two other receptors such as dopamine D2 and adenosine A2A [Navarro et al. 2008]. Interestingly, as a result, ligand bindings can produce unexpected pharmacological effects. For instance, in a heteromer complex, not only the antagonist of CB1R but also the other receptor antagonist can block the inhibitory effect of CB1R agonist. This has been demonstrated by Marcellino and colleagues when the CB1R antagonist rimonabant and the specific A2AR antagonist MSX-3 blocked the inhibitory effect of CB1 agonist on D2-like receptor agonist induced hyperlocomotion in rats [Marcellino et al. 2008]. Receptor heteromers provide better understanding of how these different neurotransmitter systems interact with each other. Compelling evidence for the existence of CB1R heteromers in striatal dendritic spines of striatal GABAergic efferent neurons, particularly at a postsynaptic location, has also been reported [Ferré et al. 2009]. The authors propose that it is likely that functional CB1–A2A–D2 receptor heteromers can be found in the dendritic spines of GABAergic enkephalinergic neurons, where they are highly coexpressed, and their analysis provides new information on the role of endocannabinoids in striatal function, which can be considered as retrograde signals that inhibit neurotransmitter release. Further evidence for the existence of D2 and CB1Rs in ventral striatum is provided by electron microscopy analysis, which confirms the relevance to the rewarding and euphoric, as well as motor effects produced by cannabis, by enhancing dopamine levels particularly in the nucleus accumbens [Pickel et al. 2006]. CB1R expression in the striatum and their role in differential signalling between different developmental stages and sensorimotor and associative/limbic circuits have also been demonstrated in a recent study [van Waes et al. 2012].

About 18.5% of people in the UK use cannabis regularly [Atha, 2005]. This is important as the strong THC variants of cannabis use have been increasing steeply, as have concerns on cannabis-related health risks, particularly for young people [Hall and Degenhardt, 2007; Potter et al. 2008; EMCDDA, 2011]. Recent epidemiological studies point towards a link between the use of cannabis and the development of a psychotic illness [Zammit et al. 2002; van Os et al. 2002; Arseneault et al. 2002; Henquet et al. 2005]. Further evidence comes from a systematic review of longitudinal and population-based studies which show that cannabis use significantly increases the risk of development of a psychotic illness in a dose-dependent manner [Moore et al. 2007].