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CBD has been touted for a wide variety of health issues, but the strongest scientific evidence is for its effectiveness in treating some of the cruelest childhood epilepsy syndromes, such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which typically don’t respond to antiseizure medications. In numerous studies, CBD was able to reduce the number of seizures, and, in some cases, it was able to stop them altogether. Videos of the effects of CBD on these children and their seizures are readily available on the Internet for viewing, and they are quite striking. Recently the FDA approved the first ever cannabis-derived medicine for these conditions, Epidiolex, which contains CBD.

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?

The evidence for cannabidiol health benefits

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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CBD is commonly used to address anxiety, and for patients who suffer through the misery of insomnia, studies suggest that CBD may help with both falling asleep and staying asleep.

The discussion on the legal status of CBD revolves mainly around the question: is it a medicine or a natural food supplement? The main difference is that medicinal drugs are considered unsafe until proven safe, whereas food supplements are considered safe until proven otherwise. As a result, the central question becomes whether or not CBD is safe for consumers (children, elderly, patients) in large and unregulated quantities. Although there is only limited knowledge about the long-term effects of chronic use, or about drug-drug interactions between CBD and other medications [36], human studies have indicated that CBD is very well tolerated even up to a daily dose of 1,500 mg [37]. Indeed, a recent World Health Organization (WHO) review concluded that “to date, there is no evidence of recreational use of CBD or any public health-related problems associated with the use of pure CBD” [38]. However, the risks to be assessed about CBD products may not have much to do with the pure compound CBD itself, but more with the unknown composition and quality of the products offered. In particular, we should be looking into the presence of contaminants in these concentrated extracts, and into incorrect or even misleading labels for the cannabinoid content of products.

Although a range of analytical methods have been published in recent years [48], there is no general agreement on which analytical method is most suitable and accurate. Additionally, there are currently no generally accepted guidelines or certifications to determine the qualifications of cannabis labs. As a result, cannabinoid analysis can differ significantly between labs [49], even when the exact same sample is analyzed multiple times [50]. This not only poses a risk to consumers (who do not know how trust the label on their product) but may also lead to business-to-business conflicts about the quality or value of intermediate products. Additionally, inaccurate analytical results may lead to legal problems if the THC content of a CBD product unexpectedly turns out to be higher than the maximally allowed limit. It seems clear that a better agreement on the conditions for lab testing of cannabinoids is urgently needed.

The fact that the maximum CBD content in an oil is limited by the THC present in the herbal material used makes it attractive to add an additional amount of purified CBD to boost the percentage advertised on the label. Unfortunately, the Novel Food Catalogue of the EU states that “extracts of Cannabis sativa L. in which CBD levels are higher than the CBD levels in the plant source are novel in food” [35]. This means that enriching a natural hemp extract with pure (often synthetic) CBD makes it a Novel Food product, with the consequence that it must undergo significant safety assessment prior to being marketed. However, it is still unclear in many EU countries if extracts with no added CBD also fall under this regime.

What Studies Tell Us

Additionally, as many as 26/46 samples (57%) had a THC content > 1%, with one sample peaking at 57.5%. In 18/46 samples (39%) the oil contained virtually only THC (with CBD < 0.1%). Although many of the samples analyzed were purposely made to contain a high THC content, it is unclear whether oil consumers are always aware they are consuming THC, and thereby exposing themselves to the adverse effects of this psychotropic compound, such as intoxication, panic attacks, or disorientation. It should be noted that although the exact legal status of CBD may be debatable, THC-rich extracts are strictly prohibited in virtually all countries.

An important issue in the discussion around cannabis-derived oils is: how much THC is a legal CBD product allowed to contain in order not to be considered a narcotic? Authorities sometimes choose to deal with these regulations in a pragmatic way, recognizing that laws once designed to control marijuana abuse may not be fully applicable to hemp. For example, in the Netherlands, a maximum level of 0.05% THC is allowed in CBD products, even though, formally, any detectable trace of THC is illegal according to Dutch narcotics laws. This approach is based on the fact that even hemp varieties of cannabis produce a small amount of THC, and therefore naturally derived CBD extracts will carry some THC in the final products.

Given the many restrictions and conditions, it can be difficult to set up a fully legal and functional pipeline for the production and sale of CBD oil. Because different countries allow different activities with regards to cultivation, processing, extracting, etc., of hemp, entrepreneurs have often set up production pipelines that span multiple countries, where hemp is cultivated in one country, while extraction takes place in another, lab testing in a third, and sales take place in yet another country. This obviously makes it harder to determine exactly where a CBD product comes from, who is responsible for its final quality, and what standards were followed. For that reason, thorough analytical testing of final products by certified third-party labs is an essential tool to guarantee the safety and composition of CBD oils.

Cannabidiol (CBD) oil is essentially a concentrated solvent extract made from cannabis flowers or leaves that is dissolved in an edible oil such as sunflower, hemp, or olive oil. Solvents used can vary from relatively innocuous organic solvents (ethanol, isopropyl alcohol) to more harmful ones (petroleum-ether, naphtha), or even supercritical fluids (butane, CO2). The exact conditions and solvents applied have a great impact on, for example, the taste, color, and viscosity of the final product. Because many other plant components are co-extracted with the desired cannabinoids present in the herbal material, these are sometimes removed by a treatment known as “winterization.” By placing the extract in a freezer (–20 to –80°C) for 24–48 h, components with a higher melting point such as waxes and triglycerides, as well as chlorophyll will precipitate, so they can be removed by filtration or centrifugation [1]. This treatment can significantly improve the taste and color of the final product.

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].

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].

In the brain, CB1Rs are found at the terminals of central and peripheral neurons, where they mostly mediate inhibitory action on ongoing release of a number of excitatory and inhibitory dopaminergic, gamma-aminobutyric acid (GABA), glutamatergic, serotoninergic, noradrenalin and acetylcholine neurotransmitter systems ( Figure 1 ). Because of the involvement of these systems they affect functions such as cognition, memory, motor movements and pain perception [Howlett et al. 2002]. The release of endocannabinoids, such as AEA and 2-AG, from the postsynaptic sites to the synaptic cleft occur in response to elevation of intracellular calcium and they then act as retrograde neurotransmitters on presynaptically located CB1Rs to maintain homeostasis and prevent the excessive neuronal activity [Howlett et al. 2002; Terry et al. 2009]. They are then rapidly removed from the extracellular space by cannabinoid transporters, often referred to as anandamide membrane transporters, which facilitate their breakdown by internalizing the molecule and allowing access to fatty acid amide hydrolase [Pertwee, 2010]. Despite its significance in the endocannabinoid system, little is known about the cannabinoid transporters.

Different strengths of street cannabis

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].

Even though cannabis has been used and cultivated by mankind for at least 6000 years [Li, 1973] our current knowledge on its pharmacological properties is based on studies which have taken place only since the end of the nineteenth century. The very first compound isolated in pure form from the plant was cannabinol [Wood, 1899]. It was initially wrongly assumed to be the main active compound of the plant responsible for its psychoactive effects [Mechoulam and Hanus, 2000]. The second compound found was cannabidiol (CBD) by Mechoulam and Shvo [Mechoulam and Shvo, 1963]. The following year in 1964, Gaoni and Mechoulam isolated the main active compound, delta-9-tetrahydrocannabinol (d-9-THC) ( Figure 1 ) [Gaoni and Mechoulam, 1964].

Most recently there have been a number of drug challenge studies with sound methodologies examining the effects of both of these compounds. Our group carried out a number of double-blind, pseudo-randomized studies on healthy volunteers who had previous minimal exposure to cannabis. All participants were administered 10 mg of d-9-THC, 600 mg of CBD and placebo (flour) in three different functional magnetic resonance imaging sessions while performing a response inhibition task, a verbal memory task, an emotional task (viewing fearful faces) and an auditory and visual sensory processing task. The overall concluding results showed that d-9-THC and CBD had different behavioural effects and also, at times, opposing brain activation in various regions [Borgwardt et al. 2008; Fusar-Poli et al. 2009; Bhattacharyya et al. 2009b; Winton-Brown et al. 2011]. D-9-THC caused transient psychotic symptoms and increased the levels of anxiety, intoxication and sedation, whilst CBD had no significant effect on behaviour or these parameters.

As d-9-THC is the main ingredient which causes the desired ‘stoned’ effect, users prefer the strains of the plant with higher THC content. Particularly over the past 15 years, such variants of the plant have been more widely available on the street ‘market’, which are usually referred to as ‘skunk’ or ‘sinsemilla’. In a study carried out by Potter and colleagues, when the potency of cannabis seized by police in England between the years of 1996/8 and 2004/5 were compared, the median content of d-9-THC was found to be 13.9% in more recent years, significantly higher than recorded 10 years previously [Potter et al. 2008]. However, the CBD content was found to be extremely low in more recent times. The authors also found that in herbal or resin forms of the drug, the average CBD content exceeded that of THC. More recently, a meta-analysis to assess the potency of cannabis from 1970 to 2009 was carried out. From 21 case series covering a number of countries, a recent and consistent worldwide increase in cannabis potency was reported [Cascini et al. 2011].