In principle, synthesis of exact copies of natural cannabinoids can be done, meaning that the synthetic cannabinoids can be similar or even identical to natural cannabinoids. However, in practice, the safety profile of synthetic cannabinoids can be different, meaning that they can lead to adverse effects. Natural cannabinoids do not pose a public threat and have been used worldwide for many years.
Synthetic cannabinoids are usually not supplemented with .flanking compounds. , something often seen for natural cannabinoids (phytocannabinoids). The entourage effect is thus not present in synthetic cannabinoids, meaning that the natural cannabinoids are often preferred over synthetic cannabinoids in medical treatment.
Endocannabinoids, as well as phytocannabinoids, can interact with more than one receptor and exhibit more than one activity which can be beneficial in normal physiology. In contrast, synthetic cannabinoids are specific for the receptor of interest and do not interact with any other receptor. This allows for synthetic cannabinoids to be useful in research but not necessarily in medical treatment. For instance, mapping the distribution of CB1 receptors can only be valid when the used probe is highly specific for CB1 and does not cross-react with any other receptor in the body (Ceccarini et al., 2015).
Another difference is that natural cannabinoids (endo- as well as phytocannabinoids) have a moderate affinity and short-lasting effect for their receptor whereas synthetic cannabinoids are often produced to have a high affinity for their receptor of interest and possess a long-lasting effect.
The analogy of the receptor CB1 being a lightbulb can help describe the difference between allosteric modulators , a full agonist , an antagonist , and a partial agonist. and this works for both natural and synthetic analogs. .
When CB1 is introduced to a full agonist like the synthetic cannabinoid Win55232-2, the CB1 lightbulb would light up to its maximum lighting. Oppositely, if introduced to the synthetic cannabinoid SR141716, an antagonist, the CB1 lightbulb would be turned off. However, if instead the CB1 lightbulb was introduced to the phytocannabinoid THC, a partial agonist, the lightbulb would only give dim lighting. If the CB1 lightbulb was introduced to an allosteric modulator, such as the phytocannabinoid CBD, the lightbulb would be provided with a dimmer or on/off switch. In the case of CBD, it does not bind directly to the activation site of CB1 but to another part of the receptor, acting as a modulator of CB1, or as a dimmer for the CB1 lightbulb.
The example above illustrates why treatment with cannabinoids is recommended, as the distinct cannabinoids influence the receptor in four different ways and thereby have different effects. However, since natural cannabis- and cannabinoids have been used globally for over 6.000 years without a single reported fatality, natural cannabinoids have a well-established safety profile and can therefore often be safer to use.