Following the discovery of THC (newsletter 4) and the endocannabinoid system (ECS) (newsletter 6), the medical industry worldwide has attempted to investigate the pharmacological interactions between cannabinoids and the human ECS. More specifically, medical research in the late 1970s was particularly interested in attempting to separate the biological activity of (some) cannabinoids with their psychoactive effects (1,2). This led to a series of studies in the coming decades, aimed at both the search of cannabimimetic compounds in different plant species (newsletter 18), as well as the development of artificial counterparts to natural cannabinoids (3). 

These new laboratory-made chemicals, called synthetic cannabinoids (SCBs), are mostly compounds with a structure similar to phytocannabinoids, but also molecules with different chemical scaffolds which are able to activate endogenous cannabinoid receptors in the ECS (3,4,5). In other words, synthetic cannabinoids are specifically manufactured to mimic the effects of natural cannabinoids, such as THC and anandamide, by interacting with the endocannabinoid receptors in the brain (1,4,5).They are often designed using THC as a model, and similarly to natural cannabinoids they present a chemical structure with 4 parts: ring, link, core, and tail (1, 4,5). These manufactured chemicals often have temporary names based on their designer/discoverer (table 1) and are only given a different label when the compounds show more pharmacological interest.

While five main classes of synthetic cannabinoids are recognized (table 2), advancement into biochemical synthesis lead to a SCBs classification based on selectivity within the ECS (3,4,6).  First generation synthetic cannabinoids (produced between the late 1970s and 1990s) are chemicals such as Nabilone and Dronabinol, that have non-selective interactions with receptors in the ECS. On the other hand, synthetic chemicals with a high selectivity for either CB1, CB2 or both CB1/CB2 receptors (exclusively) are referred to as second generation synthetic cannabinoids. In recent years, third and fourth generation synthetic cannabinoids have also been introduced. However, due to the large amount of new synthetic molecules being produced globally, this “generation” nomenclature is quickly becoming outdated, and only used to differentiate synthetic compounds between each other in the legal framework (1,2,3,5).

Today, thousands of synthetic cannabinoids have been produced, which opens the door to a lot more questions, opportunities and challenges. While on one hand the research potential of these compounds is virtually limitless, synthetic cannabinoids have been shown to have much higher affinity for ECS receptors than natural cannabinoids, making them much more potent than natural cannabinoids (8,9). In biochemistry, receptor affinity is calculated via a so-called affinity constant (Ki) where low values indicate higher affinity to a certain receptor (and therefore higher pharmacological potency). As a reference, Δ9-THC has a Ki value of around 10.2 nM for the CB1 receptor, and 24 nM for the CB2 receptor (7,8,11). Synthetic cannabinoids instead, have Ki values that can reach up to 0.04 nM for CB1 and 2.9 nM for CB2, meaning that they can bind over 100 times more tightly to both receptors than natural THC (6,7,8). Furthermore, unlike Δ9-THC which consistently show a partial binding efficacy to ECS receptors in vitro but it’s much more inconsistent in in-vivo models, SCBs regularly show a consistent much higher binding potential at both the CB1 and CB2 receptor across a range of in vitro and in vivo assays (8,9,10).

In addition, other chemicals derived by the metabolism of synthetic cannabinoids have been shown to retain higher receptor affinity than Δ9-THC and result in pharmacological and toxicological effects distinct from those induced by natural cannabinoids. For example, the metabolism of JWH-018, and AM-2201 within the body produces compounds which are still able to bind CB1 receptors with the same strong affinity (2,9). This is different from what normally happens with THC; where cannabinoid breakdown leads to new metabolites with a much lower affinity for receptors in the ECS system. 

The higher affinity for receptors allows many synthetic cannabinoids to be used in pharmacological studies involving receptor binding studies and detailed mechanisms of action of these drugs. Among the most common cannabinoids in this respect are CP‐55,940 (a non‐classical cannabinoid), WIN‐55,212‐2 (an aminoalkylindole) and methanandamide (an eicosanoid) (2,3,8). In addition, some synthetic cannabinoids have been used for medicinal purposes (8,10). Beside THC and CBD, several synthetic molecules that are CB1 receptor agonists or antagonists have shown potential for treating epilepsy, spasticity, inflammation, eating disorders, muscular pain, anxiety, depression and, occasionally, cancer (2,3,8,10). However, to this day, the side effects and exact signalling pathways of synthetic cannabinoids remain major drawbacks. Rimonabant: A selective CB1 receptor antagonist has been used to treat obesity for some time, but was withdrawn from the market because it showed severe psychiatric side effects ranging from anxiety attacks to suicidal thoughts. Nabilone was used for treatment of anorexia, PTSD (newsletter 16) and for its antiemetic effects (e. g. in cancer patients under chemotherapy) but has also been reported to increase heart rate and result in breathing difficulties if not administered correctly to patients. Dronabinol, a synthetically produced pure THC-equivalent, has shown some promising results to treat schizophrenia (newsletter 16) , muscular pain and multiple sclerosis. Similarly, chemicals derived from the metabolism of JWH-018 and JWH-073, two SCBs which have shown potential against memory loss in previous studies, also induces hypothermia and a sharp decrease in other cognitive functions (more than 60%!) on in-vivo mice models (6,7,9,11). 

Overall, synthetic cannabinoids represent a unique opportunity for pharmacological research, a much more in depth understanding of the signalling cascades that SCBs metabolism has on the body that is still needed. New “generations” of synthetic cannabinoids are showing potential for treatments in various medical fields (8,11). However, the unpredictability of side effects, together with the much higher affinity that these metabolites have to ECS receptors, make synthetic metabolites a severe risk for public health if abused recreationally (1,3,4,8,11).

In recent years, production of synthetic cannabinoids rapidly expanded on the illegal market, making uncontrolled variations of SCBs much more accessible to the general public. We will cover this topic and dive more in depth into the increasing side effects being discovered from consumption of SCBs in another newsletter.