Tetrahydrocannabivarin: The less well known cannabinoid with many potentials

Tetrahydrocannabivarin as the name itself suggest is very closely related to the best known and most studied cannabinoid tetrahydrocannabinol or THC, as THCV is structurally a propyl analogue of THC.

Tanja Bagar | Ph.D Assistant Professor, Director ICANNA - International Institute for Cannabinoids

Cannabis sativa L. is a plant that contains a wide range of diverse molecules. It is estimated that there are over 1000 bio(in)active molecules in the plant (Andre et al. 2016). The most interest is placed on the cannabinoids, the substances that bind to cannabinoid receptors and in this group THC and CBD have been well researched. However these two are only the tip of the iceberg, as there are over 140 different cannabinoids that have been isolated from cannabis. In this paper we will focus on one of the less well-known cannabinoids, that is the tetrahydrocannabivarin or THCV. 

Tetrahydrocannabivarin as the name itself suggest is very closely related to the best known and most studied cannabinoid tetrahydrocannabinol or THC, as THCV is structurally a propyl analogue of THC. As evident from the molecular structures in Figure 1, the only difference is in the length of the lipophilic alkyl chain, but their effects nonetheless strongly differ.

The content of THCV in the plant is mostly rather low, below 0,5% of total cannabinoids, however some strains/chemowars have a higher THCV content. The biosynthetic route of THCV in the plant differs from the way many other cannabinoids are synthesized. Namely THCV starts with a reaction between geranyl pyrophosphate and divarinolic acid, resulting in cannabigerovarin acid (CBGVA). From here the enzyme THCV synthase produces tetrahydrocannabivarin carboxylic acid (THCVA) from CBGVA (Mudge et al. 2004). Like other cannabinoids THCVA can be decarboxylated with heat or UV light to create THCV.

The biological effects of THCV are diverse and still subject to research. However it is known that THCV binds to both CB1 and CB2 receptors. For the docking of THCV on the CB1 receptor discrepancies have been found. Most of the in vitro studies found THCV to bind to the CB1 receptor as an antagonist/inverse agonist, meaning it binds but does not activate the downstream signaling, rather blocks it (Thomas et al. 2005; Pertwee et al. 2007).  But some in vivo studies also showed agonist binding to the CB1 receptor, it appears that its mode of action at these receptors depends also on the concentrations of THCV that is used in the studies (Pertwee et al. 1972). At the CB2 receptors the picture is clearer, THCV acts as s partial agonist in in vitro and in vivo studies (Bolognini et al. 2010). Beyond the classical two cannabinoids receptors the THCV also binds to the GPR55 receptors (the putative CB3 receptor) as an agonist, as well as the 5HT1A receptor and several subtypes of the TRP channel family.

Albeit the fact that THCV binds to the same receptor as THC, it does not exhibit any psychoactive effects, making it a good clinical candidate.

In animal studies THCV was shown to decrease appetite, increase satiety, and up-regulate energy metabolism, much to the opposite of THC, that is known as an appetite stimulant. The biological effects of THCV does far studied are showing a strong potential for its use for weight loss and management of obesity and type 2 diabetes. THCV was shown to produce hypophagic effects in both fasted and non-fasted mice (Riedel et al. 2009) and thus pointing to its potential in treating hyperphagic conditions. The effects of THCV were further studied in animal models of obesity, both diet-induced obesity and genetic obesity. Animals were orally administered dose ranges of THCV of 0.1–12.5 mg/kg once daily for 30 days and the results were compared to a potent CB1 inverse agonist (AM251). There was a significant reduction in the fat contents in both AM251 (26.4%) and THCV (31.1%) compared to the control (42.1%). The selective inverse agonist reduced mice’s body weight significantly and decreased the total food intake over the first 10 days of the study, however that was not found for THCV. There was a significant reduction in the fat contents in both AM251 (26.4%) and THCV (31.1%) compared to the control (42.1%) (Wargent et al. 2013; Tudge et al. 2015)). The selective inverse agonist reduced mice’s body weight significantly and decreased the total food intake over the first 10 days of the study, however that was not found for THCV. A strong effect of THCV was observed on the plasma glucose and insulin levels, as well as liver triglycerides. 

In another study THCV resulted in decreased food intake and body weight reduction in mice models, this effect is presumed to take place due to the interaction of THCV with the transient receptor potential cation channel subfamily V member 1 (TRPV1), also known as the capsaicin receptor (Riedel et al. 2009). THCV was also found to induce a therapeutic metabolic effect by restoring insulin sensitivity in diet-induced obese mice models s (De Petrocellis et al. 2011). More studies confirmed the potential of this cannabinoid in addressing metabolic disorders, as it was found that fasting plasma glucose levels and oral glucose tolerance test improved in mice with diet-induced obesity when plant-derived THCV was administered (Wargent et al. 2013). When it was administered peritoneally it resulted in weight loss, reduced food intake, reduced body fat content, increased energy expenditure, rapid insulin response to oral glucose tolerance test (Wargent et al. 2013), and reduced liver triglycerides (Ravinet-Trillou et al. 2004). Tetrahydrocannabivarin also shows very promising neuroprotective effects, increased GABA release from neurons, preserved nigrostriatal dopaminergic neurons and reduced microglial over-activation ((García et al., 2011) especially in models of Parkinson's disease. 

If we look at the results of the studies it seems THCV has the answers to many of the modern society problems, like obesity, insulin resistance, high triglycerides, low energy expenditure and nevronal overstimulation and deteriorating to name just a few.

THCV has an affinity for CB1 receptors and high brain penetration and produces metabolically beneficial effects and may very well be considered a great candidate for the treatment of metabolic syndrome, type 2 diabetes and some neurological conditions, either alone or as an adjuvant treatment with other therapeutic options.