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The Chemistry of Cannabis & Synthetic Cannabinoids

Cannabis & Synthetic Cannabinoids
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In recent years, there’s been an increase in the number of media reports on users of synthetic cannabinoids. Commonly referred to by names such as ‘Spice’ or ‘K2’, the most recent reported case involved five UK students being hospitalised after use. But what are the chemicals present in ‘spice’ and similar drugs, and what are the chemical compounds in cannabis that they aim to mimic? That’s what this graphic and post attempt to answer.

Let’s start with cannabis. Cannabis contains a large number of compounds known as ‘cannabinoids’. These are produced naturally by the plant, and the most important is tetrahydrocannabinol, or THC. This is the major compound in cannabis responsible for the drug’s effects. The cannabinoids in cannabis target the cannabinoid receptors; these come in two varieties, CB1 and CB2 receptors. CB1 receptors are found primarily in the brain, and it’s the interaction of cannabinoids with these receptors that is responsible for psychological effects. The CB2 receptors are found mainly in the immune system, and are partly responsible for the anti-inflammatory and potential medicinal benefits of cannabis (though in some cases, these are also due to interaction with CB1 receptors).

Why do we even have receptors that the chemicals in cannabis are capable of activating? The cannabinoid receptors are usually activated by what are known as ‘endogenous cannabinoids’ – in other words, cannabinoid chemicals we produce in our bodies. One of these is anandamide, a neurotransmitter which has a number of roles, including in pain, appetite, and memory. Research into the roles of endogenous cannabinoids is still continuing – they were only discovered after investigation into the effects of THC in the body, hence why the class of chemicals and the receptors are named after cannabis.

Synthetic cannabinoids are a class of compounds originally synthesised to further investigate cannabinoid receptors, and the potential medicinal benefits of cannabis. None of them are found naturally in cannabis – they are all the product of laboratory synthesis. Work on them began in the 1970s, and initially they were structurally similar to THC. However, since then, a wide variety of compounds with structures much different from that of THC have been synthesised. What they do all have in common is their interaction with cannabinoid receptors.

The manner in which the synthetic cannabinoids can be grouped is variable. Some studies place them in three very broad categories: classical cannabinoids, which are structurally similar to THC; aminoalkylindoles, the largest group, which can be split into further subcategories; and non-classical cannabinoids, which include compounds such as cyclohexylphenols. Other classification systems use seven or more groups which are more structurally specific. The issue with the large number of new & different synthetic cannabinoids being produced for both research and illicit use is that in cases, they defy categorisation in some of these systems, which has led some researchers to suggest that they should instead be categorised by biological activity.

In terms of how they act, there are marginal differences between natural cannabinoids like THC and synthetic cannabinoids. Whilst they act on the same cannabinoid receptors, THC is only a partial agonist, whilst synthetic cannabinoids used for illicit purposes are full agonists. These terms will require a little explanation for those unfamiliar with them. An agonist is a molecule that binds to a receptor and activates it; a partial agonist does not induce the maximum response, however, whereas a full agonist can. The fact that synthetic cannabinoids are full agonists means that their potency compared to THC is higher; animal studies have suggested that their potency can be 2 to 100 times that of THC.

The first isolation of synthetic cannabinoids from ‘spice’ was reported in 2008, but reports of their use in ‘legal highs’ precede this. With cannabis classified as an illegal drug in many countries, these synthetic cannabinoids may seem an attractive substitute to many would-be cannabis smokers. The synthetic cannabinoids themselves are solids, but are dissolved in solvents then sprayed onto dried herbs, which can then be smoked. However, the various synthetic cannabinoid compounds were not originally synthesised with human consumption in mind. As such, they have not undergone any form of safety testing, and little is known about the scope of their effects in humans.

That probably makes it obvious why there are concerns over the use of synthetic cannabinoids, but what are the specific effects they’ve been linked with? As stated, there haven’t been any controlled studies on humans, so what we know about their effects is limited to case reports from hospitalisations. These, however, seem to suggest that adverse effects from synthetic cannabinoids are often much more severe than those seen in studies with THC, and can include nausea & vomiting, various psychological symptoms, seizures, and in more severe cases acute kidney failure. Some cases of hospitalisation after the use of synthetic cannabinoids have also led to death. There is no form of antidote for synthetic cannabinoid use.

You might wonder why synthetic cannabinoids aren’t more tightly regulated, considering that the compounds have undergone no safety testing and there is concern over their effects. The issue is that their regulation is something of a game of cat & mouse. A number of synthetic cannabinoids are controlled in many countries – but those producing them simply switch to structurally similar compounds that are yet to be placed under legislation. In the US, the DEA banned the first synthetic cannabinoids in 2011, and since then well over 250 new, uncontrolled compounds have cropped up to take their place.

In some countries, such as the UK, a generic approach to regulation is adopted, whereby all compounds derived from a certain structural template are classified as class B drugs. This covers a large range of synthetic cannabinoids, and also has the advantage that it pre-emptively bans any compounds that are derivatives of the same structural template. However, even this method is not foolproof – several synthetic cannabinoids have been synthesised with a chemical structure that does not fall under current UK legislation. In some countries, this generic approach is not possible for legal reasons.

The use of synthetic cannabinoids really is something of a lottery. There’s no way of knowing exactly what synthetic cannabinoids are present in a mixture without analytical testing, and the quality of the products, as they are unregulated, often does not meet pharmaceutical standards. Additionally, they can be contaminated by other byproducts from the reactions used to synthesise them. Due to the manner in which ‘spice’ is produced, by spraying with synthetic cannabinoids, there’s also the possibility that it can be distributed unevenly, which can lead to higher than intended doses being ingested. Overall, it’s clear that the perception of synthetic cannabinoids as a ‘safe’ cannabis alternative is a flawed one.

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References & Further Reading