Cannabis doesn’t actually produce THC or CBD. The plant produces all cannabinoids in an acid form. Instead of making THC and CBD directly, it synthesizes tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA) from their cannabigerolic acid (CBGA) precursor.

THCA is not psychoactive—it does not activate CB1 cannabinoid receptors in the brain. In order to make psychoactive THC from THCA, one needs to heat it. This can be done by smoking or vaporizing raw flower, baking edibles, or heating cannabis in a process known as decarboxylation. When smoking cannabis, it is estimated that more than 95 percent of the THCA is converted to THC. If so, a cannabis smoker might inhale the small amount of remaining THCA, which could also impart a therapeutic effect.

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According to several doctors, THCA shows great promise in the treatment of epilepsy. Preclinical research indicates that THCA may be anti-inflammatory and may reduce nausea. One of the most signficant features of THCA is its apparent ability to work at very low doses. The therapeutic potential of THCA is all the more noteworthy given that this compound is more readily available than THC or CBD because of the ubiquity of the raw marijuana plant.

Clinical Use Of THCA

Clinical experience is the best place to start. Dr. Dustin Sulak and Dr. Bonni Goldstein have both reported on the use of THCA in the treatment of patients. In a recent publication, Sulak, Goldstein, and Dr. Rubel Saneto describe four case reports of patients using THCA along with other treatments (conventional anti-epileptic drugs as well as cannabis). Among these patients, small doses—around 0.1-1 mg/kg/day THCA1—were used, corresponding to 0.01 to 0.1 percent of the patient’s body weight in THCA. For a child weighing 50 pounds, this entails between 2-23 milligrams of THCA in a day.

By contrast, studies with Epidiolex, a pure (99.5 percent) CBD sublingual spray, start at a dose of 5 mg/kg/day and usually increase to 25 mg/kg/day. The aforementioned doses of THCA are 10-100 times lower.2

THCA is typically administered along with other components of cannabis in a tincture via an under-the-tongue dropper or spray. Sulak’s article indicates that higher doses of THCA did not generally improve the response, with one patient getting worse after increasing the dose of THCA. Sulak also found that specific terpenes along with THCA in a given cannabis strain can contribute signficantly to the anti-epileptic effect. (Linalool, in this case, was needed for the anti-epileptic effect.)

• Related Story: Marijuana’s THC May Help Improve Memory In Older Adults

Dr. Goldstein told Project CBD that daily consumption of 10-20 mg. of THCA was effective in reducing pain in some of her patients with arthritis and irritable bowel syndrome. For one patient with Alzheimer’s disease, THCA improved cognitive symptoms and allowed the patient to reduce the use of other drugs.

Dr. Sulak also spoke with Project CBD, saying that a higher dose of 2 mg./kg. of THCA combined with THC is sometimes effective for seizures, pain, and arthritis. For neurological, about 1 mg. of THCA and THC used 2-3 times a day has helped some of his adult patients. In one teenager, a very low dose of THCA prevented severe refractory migraines.

Anecdotal reports from other sources indicate that a 10:1 CBD:THCA ratio can be effective for some epileptic children when a high CBD/low THC cannabis oil preparation does not deliver satisfactory results. One seven-year-old patient, weighing 42 pounds, has been seizure free for the past two-and-a-half years since he’s been on a dosage regimen of 50 mg./day of CBD and 10 mg./day of THCA.

THCA In The Lab

Thus far, preclinical research into THCA has been very confusing. Erin Rock and other scientists at the University of Guelph in Ontario have demonstrated that low doses of THCA—about 10-100 times lower than the requisite dose of THC—prevent nausea in rats. In addition, they found that THCA synergizes with CBDA, which is also a potent antiemetic compound. It is possible that the anti-nausea effect of smoking cannabis is partly attributable to the small amount of THCA that remains when cannabis is burned.

Curiously, THCA’s effect in the Guelph study was prevented by blocking the CB1 cannabinoid receptor. This is surprising, given that THCA isn’t known to bind to CB1 and doesn’t cause psychoactive effects like THC does when the latter binds to CB1. Yet Rock et. al. did not observe any effects from THCA that they could attribute to central CB1 activity. A possible explanation for this finding is that Rimonabant, the experimental drug they used to block the CB1 receptor, may have inhibited THCA’s effects through a different channel or receptor, such as GPR55 (which is activated by Rimonabant). When asked by Project CBD, Dr. Rock indicated that they are uncertain as to how THCA prevents nausea, and that it may very well be an off-target or peripheral effect.

A study by Rosenthaler and a group of Austrian scientists surmised that THCA has a greater binding affinity to the CB1 receptor than THC does. It may be that this study was flawed (their data also suggested—likely incorrectly—that CBN, a breakdown product of THC, binds to CB1 more potently than does THC). But it also might be the case that THCA acts primarily on peripheral CB1 receptors outside the brain and central nervous system. The main difference between THCA and THC could be related to how these compounds are distributed throughout the body. Another explanation might derive from an inconsistancy between two molecular isoforms of THCA—THCA-A and THCA-B—which could give rise to different results (see sidebar).

How Does THCA Work?

So how does THCA confer its effects? Through which biochemical channels does THCA act? The only receptor to which THCA is known to potently bind is TRPM8—the receptor that makes mint feel cold. THCA is a strong antagonist of TRPM8. But there is no research to indicate that inhibiting TRPM8 prevents nausea or reduces seizures, so this does not explain the clinically observed effects of THCA.

At higher concentrations, THCA also may activate TRPV4, a heat-sensing receptor, and TRPA1, a receptor that mediates the edgineß of spices such as mustard and cinnamon.

THCA may also convey therapeutic effects by inhibiting the metabolic enzyme MAGL that breaks down the endogenous cannabinoid 2-AG; this would result in higher levels of 2-AG, which activates both CB1 and CB2 cannabinoid receptors throughout the brain and body.

In these preclinical tests, THCA was about 10 times more potent when used as a whole-plant extract rather than as an isolate.4 But this evidence is based on only a few studies performed in cell cultures, which does not neceßarily translate to clinical experience.

Other data from preclinical work suggests that THCA may be an anti-inflammatory compound that protects against cancer, but this work is an unconvincing explanation of clinical reports. One study on THCA and breast cancer required a high concentration of THCA, about 1000 times more than the concentration in the blood of Dr. Sulak’s patients. Another study suggested that THCA was a much weaker antioxidant than THC or CBD and that THCA is only slightly neuroprotective at similarly high doses. Two studies on inflammation revealed that THCA does not inhibit COX-2, an inflammatory enzyme blocked by ibuprofen and aspirin, and high doses of THCA were required for an anti-inflammatory effect.

The fact that doctors and patients are reporting significant health-positive effects from THCA at very low concentrations underscores that there is much more to understand about THCA. The properties of THCA indicated by preclinical research may be relevant to cannabinoid medicine in the future, but they do not explain the remarkable results with low doses of THCA that patients are experiencing today.

This story originally appeared on Project CBD.