Cannabinoids like Δ9-tetrahydrocannabinol (THC) occupy cannabis as acidic forms—in this case, Δ9-tetrahydrocannabinolic acid (THCA). Consumers decarboxylate THCA to THC when combusting, vaporizing, or otherwise heating the material. However, acidic cannabinoids may confer unique benefits in their own right. With this in mind, Nadal et al  investigated the activity of THCA and other phytocannabinoids at a brain receptor associated with neuroprotection: peroxisome proliferator-activated receptor gamma, or PPARγ.
The researchers describe PPARγ as the “master regulator of lipid metabolism and glucose homeostasis” with a “key role in inflammatory processes and neurodegenerative diseases including Huntington’s disease.” Specifically, PPARγ receptor agonists (activators) may improve mitochondrial dysfunction, reduce inflammation, and help prevent oxidative damage.
The study authors used counter-current chromatography to purify (95%+) the following phytocannabinoids from three different cultivars:
- THC and THCA
- Cannabidiol (CBD) and cannabidiolic acid (CBDA)
- Cannabigerol (CBG) and cannabigerolic acid (CBGA)
They quantified cannabinoids with gas chromatography-mass spectrometry (GC-MS). The experiment proceeded with cell lines (in vitro) as the researchers cultured various cell lines, namely human kidney cells (HEK-293T), neuronal cells with Huntington’s disease (STHdhQ7/Q7 and STHdhQ111/Q111) and neuroblastoma cells (Neuro-2a (N2a) cells).
Various tests were performed on each. These include tests for PPARγ binding activity, tests for mitochondrial biogenesis (increasing mitochondrial mass), and several tests to gauge neuroprotection. For example, for neuroprotection, the researchers added phytocannabinoids to the neuronal cells for 48 hours in the presence or absence of a PPARγ antagonist (receptor blocker). The authors also induced serum deprivation and cytotoxicity in the neuronal cell lines.
Overall, the researchers note, “Cannabinoid acids bind and activate PPARγ with higher potency than their decarboxylated products.” This was true across cannabinoids.
Other key findings emphasize the efficacy of THCA. For example, THCA significantly increased mitochondrial mass in neuroblastoma cells, effectively reducing their dysfunction. In the STHdhQ111/Q111 (neuronal) cell lines suffering serum deprivation, THCA significantly mitigated cytotoxicity. The same was true when defending against the toxicity of an adenovirus in N2a cells.
The benefits were not significant, however, in the presence of the PPARγ antagonist. Interestingly, THCA is not known to bind to endocannabinoid receptors, but does appear to bind to PPARγ receptors. Compared to THC, its binding at this location was 20-fold higher. This is enough to consider THCA a potent PPARγ agonist. In fact, THCA was more potent than the control medication rosiglitazone.
The researchers confirmed their findings in vivo. Ultimately, they conclude that THCA is “worth considering for the treatment of Huntington’s disease and possibly other neurodegenerative and neuroinflammatory diseases.” 
- Nadal X, et al. Tetrahydrocannabinolic acid is a potent PPARγ agonist with neuroprotective activity. B J Pharmacol. 2017;174:4263-4276. [Impact Factor: 7.730; Times Cited: 46 (Semantic Scholar)]