Is there a difference between natural and synthetic cannabinoids?

In principle exact copies of naturally occurring cannabinoids can be synthesized. Therefore, synthetic cannabinoids are not necessarily different from natural cannabinoids. However, in practice synthetic cannabinoids are produced to be more specific and more powerful than natural cannabinoids, which can have a dramatic effect on their safety profile.

Entourage effect

Although exact copies of natural cannabinoids can be synthesized, natural cannabinoids from plants or extracts are flanked by numerous other compounds such as other cannabinoids or terpenes whereas synthetic cannabinoids usually are not.

Like the main ingredient / the cannabinoid of interest, these other compounds also bind one or more cannabinoid receptors and will therefore alter the effect that the cannabinoid of interest has.

Although it is not exactly known how this so called ‘entourage effect’ works, it is known that it consistently improves the therapeutic potential of cannabinoids (Gallily et al., 2015; Russo, 2011; Russo and Guy, 2006).


Natural cannabinoids typically bind to more than one receptor and therefore exert more than one effect. While this ‘promiscuity’ of natural cannabinoids may be very useful in normal physiology this can frustrate research attempting to elucidate the exact mechanism behind a disease or a therapy. Therefore, for research purposes, synthetic compounds / cannabinoids that are highly specific for a particular receptor can be very useful. For instance mapping the distribution of CB1 receptors can only be done faithfully 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).


Natural cannabinoids typically are gentle modulators of receptor activity that have a moderate affinity for their receptor that is short-lasting and can be washed away by other compounds / modulators. Synthetic cannabinoids are often designed to have a high affinity for their receptor and have a lasting effect.

THC for example is a partial agonist for CB1. If CB1 were a car engine, THC would put it in first gear. It’s synthetic analogue, Win55212-2 is a full agonist, which would put CB1 in high gear with a brick on the accelerator. SR141716 is a synthetic CB1 antagonist, which would slam on the break and bring the CB1 engine to a full stop. CBD does not seem to bind directly to the activation site of CB1 but to other parts of the receptor, thereby modulating or 'steering' the function of CB1 (see figure below).


Although synthetic cannabinoids can be very useful in basic research to elucidate molecular mechanisms in physiological processes, they can be dangerous if not lethal in clinical use / humans. For instance, rimonabant / SR141716 was introduced as an anti-obesity drug but subsequently pulled of the market for its potential to trigger serious psychiatric side effects or even suicide. With the advent of both recreational and medicinal cannabis the market is increasingly flooded with synthetic cannabinoids. This is at least partially due to the fact that synthetic compounds can be patented and therefore more profitable than natural cannabinoids. As a result serious injuries and even fatalities due to synthetic cannabinoid use are now reported almost on a daily basis (Adedinsewo et al., 2016; van Amsterdam et al., 2015; Babi et al., 2017; Barceló et al., 2017; Buyukbese Sarsu, 2016; Cha et al., 2015; Clark et al., 2015; Degirmenci et al., 2015; Demir et al., 2017; Efe et al., 2017; Ezaki et al., 2016; FuNADA and Takebayashi-Ohsawa, 2017; Karass et al., 2017; Kırgız and Kaldırım, 2017; Kusano et al., 2017; Mansoor et al., 2017; McIlroy et al., 2016; Moeller et al., 2017; Monte et al., 2017; Öcal et al., 2016; Ozturk et al., 2017; Raheemullah and Laurence, 2016; Samra et al., 2017; Shanks and Behonick, 2016; Waugh et al., 2016; Zarifi and Vyas, 2017).

Natural cannabis / cannabinoids has been used around the world for over 6.000 years without a single reported fatality and are thus far, far safer than synthetic cannabinoids.


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