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cbd oil pdf

Determining risks and benefits through proper clinical trials remains highly desired, but these will take considerable time and funds. As a result, clinical data will not appear any time soon, while patients will not simply stop using the many CBD products to which they have become accustomed. Taking back regulatory control over CBD could therefore start with a more short-term and achievable approach, i.e., demanding accurate and proper labeling, reflecting in detail what each product does and does not contain, and how it was manufactured. For a clearer judgment of the potential therapeutic effects, the risks, but also the legality of a cannabis extract, it is important to know its exact composition. After all, published data from around the world has taught us that misleading labels as well as harmful contaminants are real and actual problems for CBD products. The analytical methodology and the third-party labs needed for this approach largely already exist, and could easily be optimized to quickly get a better grip on the unrestrained cannabinoid market. This approach would hold each producer strictly accountable for the quality and safety of their own products, as long as there are real legal consequences for those businesses that break the rules. Add to this a system for regular professional audits and inspections, and a crackdown on unsubstantiated health claims, and we have a reasonable system to ensure that CBD can be used responsibly by those who need it, until much needed clinical data become available.

Recently, an interesting study performed in the Netherlands highlighted multiple issues that may be extrapolated to CBD products elsewhere [51]. In this study, 46 different cannabis oil samples were collected directly from patients and analyzed for cannabinoid content. The obtained samples were home-made (n = 29) or purchased from a (web) store (n = 17). For 21 of the 46 products (46% of all samples), label information was available on CBD/THC content, so that the claimed content could be compared to the analyzed content as determined in the study. Results are shown in Table 1. In many cases the analyzed cannabinoid content strongly differed from the claimed content on the label, while in 7 samples no cannabinoids (CBD or THC) were found at all. Such deviations were found in home-made as well as commercially obtained products.

© 2018 The Author(s) Published by S. Karger AG, Basel


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.

Another interesting observation was the presence of high levels of non-decarboxylated cannabinoids in multiple samples. It is well known that CBD and THC are not produced as such by the metabolism of the cannabis plant. Instead, cannabinoids are excreted in the form of carboxylic acids such as CBD-acid and THC-acid [52]. The physiological effects of these “acidic” cannabinoids have been studied only to a very limited extent. Only after proper heating (e.g., during smoking, vaporizing, or baking with cannabis) are these natural precursors rapidly converted into the more well-known CBD and THC, respectively. This process is called decarboxylation [52]. Although decarboxylation also takes place during the production of cannabis oils (e.g., during the evaporation of solvents, or during a separate decarboxylation step as part of the production process), 7/46 samples (15%) contained > 25% of its cannabinoid content in the form of acidic cannabinoids, indicating poor control over the decarboxylation process. To address the issue, some producers simply add up the content of CBD and CBD-acid in order to boast a higher “total CBD” content on the label, while advertising this as “raw CBD.”

Today, CBD is used for the treatment of a wide range of medical conditions. This started with the somewhat serendipitous discovery (by parents experimenting with self-medication for their children) that CBD had a therapeutic effect on a serious form of epilepsy in children, called Dravet syndrome [8]. This effect is now under clinical investigation with the pharmaceutical CBD product Epidiolex®, which is currently in phase 3 trials with encouraging results [9, 10]. The media attention generated by its effect on severely ill children gave CBD the push needed to become a much desired medicine almost overnight [11]. Other medical indications that may be treated with CBD, and are supported to some extent by clinical proof, include Parkinson’s disease [12], schizophrenia [13], and anxiety disorder [14]. However, although research into the therapeutic effects of CBD is rapidly increasing, most current uses of CBD are not (yet) supported by clinical data. The popular use of these products means that physicians may be confronted with the effects of CBD oil even when they do not prescribe it themselves.

Increasingly, CBD oil is also being promoted as a prophylactic treatment in order to prevent certain diseases from developing at all. The argument used is that the human endocannabinoid system is involved in basic life functions such as appetite, immune response, reproduction, and pain management [20]. Because CBD functions as an indirect antagonist to human CB1 and CB2 receptors [21], it is reasoned that the presence of CBD prevents them from being overly activated, thereby protecting the nervous and immune systems from everyday stress. Furthermore, CBD is known to be a reasonably potent antioxidant, which further helps to protect against stressful influences [22]. Although this clearly increases the market for CBD products, it also further erodes the scientific basis for the therapeutic use of CBD. After all, it is hard to prove scientifically that a disease was prevented by the use of a health-promoting product.

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."

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.

How is cannabidiol different from marijuana?

CBD may offer an option for treating different types of chronic pain. A study from the European Journal of Pain showed, using an animal model, CBD applied on the skin could help lower pain and inflammation due to arthritis. Another study demonstrated the mechanism by which CBD inhibits inflammatory and neuropathic pain, two of the most difficult types of chronic pain to treat. More study in humans is needed in this area to substantiate the claims of CBD proponents about pain control.

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.

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?

These findings suggest that current trends for preferring higher THC content variants carry significant health risks, particularly to those who are susceptible to its harmful effects. Indeed, Morgan and colleagues carried out a study on 120 current users, which included 66 daily and 54 recreational users, whose hair analyses revealed their THC and CBD amounts. The study found that higher THC levels in hair in daily users were associated with increased depression and anxiety, as well as poorer prose recall and source memory [Morgan et al. 2011]. However, higher CBD in hair was associated with lower psychosis-like symptoms and better recognition memory. In relation to people with psychosis, health risks are even higher with stronger variants of the plant. In a recent study of people with a first episode of psychosis, it was found that patients used higher-potency cannabis for longer durations and greater frequency compared with a healthy control group [Di Forti et al. 2009].

In relation to the imaging data, during the response inhibition task, relative to placebo, d-9-THC attenuated the engagement of brain regions that normally mediate response inhibition, whilst CBD modulated activity in regions not implicated with this task [Borgwardt et al. 2008]. During the verbal learning and retrieval of word pair tasks, d-9-THC modulated activity in mediotemporal and ventrostriatal regions, whilst CBD had no such effect [Bhattacharyya et al. 2009b]. During an emotional processing task d-9-THC and CBD had clearly distinct effects on the neural, electrodermal and symptomatic response to fearful faces [Fusar-Poli et al. 2009]. Our results suggest that the effects of CBD on activation in limbic and paralimbic regions may contribute to its ability to reduce autonomic arousal and subjective anxiety, whereas the anxiogenic effects of d-9-THC may be related to effects in other brain regions. During the auditory task, again these two compounds had opposite effects in the superior temporal cortex when subjects listened to speech and in the occipital cortex during visual processing [Winton-Brown et al. 2011].

The involvement of the particular neural regions and the neurotransmitter systems here is significant due to the fact that the very same brain areas and neurotransmitter systems are also implicated in psychoses, particularly in schizophrenia [van Os and Kapur, 2009; Smieskova et al. 2010; Stone, 2011].

Table 1.

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, only a small minority develop a full-blown psychotic illness in the form of schizophrenia or bipolar disorder, whilst a larger group, ranging from 15% to 50%, experience transient psychotic symptoms of brief duration, from a couple of hours to up to a week, and usually recover without requiring any intervention [Thomas, 1996; Green et al. 2003; D’Souza et al. 2004, 2009; Morrison et al. 2009]. Indeed drug challenge studies with d-9-THC on healthy volunteers have shown a broad range of transient symptoms, behaviours and cognitive deficits ranging from anxiety to psychosis to transient memory disturbance [D’Souza et al. 2004; Curran et al. 2002; Morrison et al. 2009]. The clinical picture of transient psychosis can be indistinguishable from a frank acute psychosis with delusions and hallucinations, except for its short duration.

Chemical structures of delta-9-tetrahydrocannabinol and cannabidiol.

Most recently it has been shown that CB2Rs form heteromers with CB1Rs in the brain and the agonist coactivation of CB1Rs and CB2Rs results in negative crosstalk in AKT1 phosphorylation and neurite outgrowth [Callén et al. 2012]. The authors point out that there is a bidirectional cross antagonism which involves the antagonists of either receptor to block the other. It is suggested that these data illuminate the mechanism by which CB2Rs can negatively modulate CB1R function.