otential entourage effects either kinetically or dynamically with their better-studied de-carboxylated metabolites.
Here is some of the most compelling evidence that shapes what we know about the carboxylic acid forms to date: both THCA and CBDA independently of any other phytocannabinoid, provide significant anti-nausea and anti-vomiting effects. In rats, THCA appears to be a considerable anti-nausea and anti-vomiting compound. In a study conducted in 2013, researchers determined not only that THCA was more potent compound in this regard than THC but also that THCA apparently mediated this response via 5HT1a (aka serotonin) receptors rather than the CB1 (cannabinoid) receptors whereby THC appears to exert its own anti-nausea effects as shown in other animal models (Rock 2013).
Researchers repeated similar experiments with CBDA as well, demonstrating that CBDA reduced both toxin and motion-induced nausea and vomiting in rats, via an as-yet-to-be-determined enhancement of 5HT-1A serotonin receptor activation (Bolognini et al 2013). Unlike the THCA experiment– which showed THCA and THC exerting anti-nausea effects via wholly different receptor mechanisms–CBDA appears in vivo and in vitro to work pharmacologically more similarly to CBD (e.g. both via serotonin-receptor activation), though CBDA was shown to be more potent than CBD in its serotonin-receptor-mediated effects.
Additionally, CBDA and THCA have been shown in vitro to block, in varying degrees, both cyclooxygenase (COX) enzymes 1 and 2, which are each distinct mediators of inflammation and pain secondary to inflammation. Non-steroidal anti-inflammatory (NSAID) drugs such as acetylsalicylic acid (aspirin), ibuprofen, naproxen, indomethacin, and diclofenac all work via COX 1 and 2 inhibition, and, like CBDA and THCA, contain a carboxylic acid group in their structures that suggests this part of the molecule is integral to the way they work.
In one assay, CBDA but not THCA significantly inhibited both COX 1 and 2-mediated oxidation activity, with the CBDA showing a strong preference for inhibiting COX 2 specifically (Takeda et al. 2008).
A second study demonstrated that both THCA and CBDA inhibited COX 1 significantly but only THCA inhibited COX 2, and by only a little over 30% (Ruhaak, L. et al 2011).
Both studies showed that the carboxylic acid forms CBDA and THCA had stronger overall COX-inhibiting activity than their de-carboxylated forms CBD and THC, however. More research is needed to clarify the role the acidic cannabinoids play in moderating inflammation and determine whether or not they may be safer alternatives for this than NSAIDs, which have well-known dose-dependent or long-term use detrimental effects on the gastrointestinal and cardiovascular systems due to their COX inhibition.
Lastly, both CBDA and THCA show in vitro activity at some of the various cation channel receptors collectively known as transient receptor potentials that play important roles in pain and inflammation signal transduction such as TRPV1 and TRPV4(the “vanilloid” type); TRPA1(the “ankyrin” type) and TRPM8 (the “melastatin” type). They can block, activate, or de-sensitize these to activation by another activator (Cascio and Pertwee 2014). These are likely additional mechanisms by which the carboxylic acid forms of the cannabinoids work independently of their de-carboxylated forms to moderate pain and inflammation both centrally and peripherally.
The carboxylic acid cannabinoids CBDA and THCA are likely to be important contributors to the relief of nausea, inflammation, and pain that humans have attributed to the cannabis plant for millennia. What makes them worth studying individually today are not only their individual roles within the entourage of effects that cannabis is so well known for, but also in their ability to relieve nausea or pain alone while bypassing the sometimes debilitating or unwanted psychoactive effects produced by cannabinoids like THC that activate the CB1 receptor.
The recent popularity of websites and electronically-published books extolling the benefits of